Chloro- and alkoxy-substituted-2-chloro-4-aminodquinazolines

ABSTRACT

2,4-Diaminoquinazolines of the formula ##STR1## wherein Y 1  is hydrogen or chloro, Y 2  is OR, Y 3  is hydrogen or OR such that when Y 1  is hydrogen, Y 3  is OR and when Y 1  is chloro, Y 3  is hydrogen or OR, and the pharmaceutically acceptable salts thereof; R represents an alkyl group having from one to three carbon atoms; 
     taken separately, R 1  and R 2  are each hydrogen, alkyl having from one to five carbon atoms, cycloalkyl having from three to eight carbon atoms, alkenyl or alkynyl each having from three to five carbon atoms or hydroxy substituted alkyl having from two to five carbon atoms, when taken together with the nitrogen atom to which they are attached R 1  and R 2  form a substituted or unsubstituted heterocyclic group optionally containing an atom of oxygen, sulfur or a second atom of nitrogen as a ring member; their use as antihypertensive agents, pharmaceutical compositions containing them and intermediates for their production.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 126,838 filedMar. 3, 1980, U.S. Pat. No. 4,287,341, which in turn is acontinuation-in-part of application Ser. No. 90,313, filed Nov. 1, 1979,and now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain 2,4-diaminoquinazolines. Particularly,the invention relates to certain 7-alkoxy-2,4-diaminoquinazolines whichare further substituted by a 6-chloro group and/or an 8-alkoxy group,their use as antihypertensive agents, pharmaceutical compositionsthereof and intermediates for their production.

2. Description of the Prior Art

U.S. Pat. Nos. 3,511,836; 3,635,979 and 3,663,706 disclose6,7-dimethoxy-2,4-diaminoquinazolines of the formula ##STR2## where Z isa nitrogen-containing heterocyclic group. One of these compounds,2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6,7-dimethoxyquinazoline, is aclinically useful antihypertensive agent and is marketed under thegeneric name "prazosin," the pharmacology of which is discussed inConstantine et al., "Hypertension: Mechanisms and Management," edited byOnesti, Kin and Moyer, Grune and Stratton, 1973, pp. 429-444.

U.S. Pat. No. 3,669,968 and U.S. Pat. No. 3,769,286 disclose6,7,8-trialkoxy-2,4-diaminoquinazolines in which the 2-amino group issubstituted by certain alkyl and hydroxy substituted alkyl groups or isa heterocyclic group such as piperidino or 4-substituted piperazino. Oneof these compounds is known by the generic name "trimazosin" and has theformula ##STR3## Trimazosin is also an active antihypertensive agent,see e.g., Vlachikis et al., Current Therapeutic Research, 17, 564(1975). However, it is less potent than prazosin. Althuis et al., J.Med. Chem., 20, 146 (1977) have shown the 6-O-demethyl derivative is amajor metabolite of prazosin of considerably lower blood pressurelowering activity. The 7-O-demethyl derivative is a less prevalentmetabolite.

U.S. Pat. No. 3,920,636 and U.S. Pat. No. 4,044,135 disclosehomopiperazinoquinazoline compounds as antihypertensive agents.

Several patents have issued which disclose antihypertensive compounds ofthe general formula ##STR4## U.S. Pat. No. 4,001,237 claims compoundswherein R^(a) is an oxazole, isoxazole, thiazole or isothiazole radical.

In U.S. Pat. No. 4,001,238, such compounds are disclosed wherein R^(a)is of the formula ##STR5##

U.S. Pat. No. 3,780,040 discloses 3,4-dihydroquinazoline analogs of theabove formula wherein R^(a) is 2-thienyl.

In U.S. Pat. No. 4,026,894 and U.S. Pat. No. 4,112,097, R^(a) is a2-tetrahydrofuryl or 2-tetrahydropyranyl moiety. U.S. Pat. No. 4,060,615claims compounds in which R^(a) is cycloalkyl having 3 to 8 carbon atomsand cycloalkenyl having 4 to 8 carbon atoms. U.S. Pat. No. 4,101,548 isconcerned with 1,2,3-thiadiazole amides of the above formula whereinR^(a) is ##STR6## and R^(b) is hydrogen, lower alkyl, NH₂ or NHCO₂ R^(c)in which R^(c) is lower alkyl.

6,7-Dimethoxy-2-(4-thiomorpholin-1-yl) 4-aminoquinazolines andderivatives in which the 2-substituent is ##STR7## are disclosed asantihypertensive agents in U.S. Pat. No. 4,115,565.

British Pat. No. 1,530,768 discloses prazosin analogs in which the2-amino group is of the formula ##STR8## where R^(e) is phenyl,substituted phenyl, furyl, thienyl or 5-alkylthio-1,3,4-oxadiazol-2-yl.

French Pat. No. 2,321,890 discloses analogs of prazosin in which the2-amino substituent is a piperidino or piperazino group substituted inthe 3 or 4 position.

The compounds of the invention are highly potent antihypertensive agentshaving improved duration of action since they are not susceptible tometabolic demethylation at the 6-position with resultant loss ofactivity as is the case with prazosin. In addition, the inventioncompounds have improved water solubility when compared to prazosin. Theycan therefore be administered intraveneously, particularly for emergencypurposes and are uniformly absorbed by all patients.

SUMMARY OF THE INVENTION

The present invention discloses new 2,4-diaminoquinazoline compounds andprocesses for their production. The new 2,4-diaminoquinazolines possessvaluable pharmacological properties and other aspects of the inventionrelate to pharmaceutical compositions for oral or parenteraladministration to a mammal comprising one or more of said new compoundsand a pharmaceutically acceptable carrier, as well as a method fortreating hypertension which comprises orally or parenterallyadministering to mammals in need of such treatment an antihypertensiveeffective amount of a compound of the invention.

The compounds of the invention are also useful for their vasodilationproperties, as antiglaucoma agents and in the treatment of congestiveheart failure.

The novel compounds disclosed are of the formula ##STR9## wherein Y¹ ishydrogen or chloro, Y² is OR and Y³ is hydrogen or OR such that when Y¹is hydrogen, Y³ is OR and when Y¹ is chloro, Y³ is hydrogen or OR, andthe pharmaceutically acceptable acid addition salts thereof;

R is alkyl having from one to three carbon atoms;

R¹ and R² are the same or different and when taken separately are each amember selected from the group consisting of hydrogen, alkyl having from1 to 5 carbon atoms, cycloalkyl having from 3 to 8 carbon atoms; alkenylhaving from 3 to 5 carbon atoms, alkynyl having from 3 to 5 carbonatoms, hydroxy substituted alkyl having from 2 to 5 carbon atoms andwhen taken together with the nitrogen atom to which they are attached R¹and R² form ##STR10## where X¹ is a member selected from the groupconsisting of S(O)_(t), CHOR⁶, --(CH₂)_(p) -- and CHR⁷, and X² is amember selected from the group consisting of X¹, O, NR³, NCOR⁴ andNCOOR⁵, where

m is 2 or 3,

n is 2 or 3,

p is 1 to 3,

t is 0, 1 or 2;

R³ is a member selected from the group consisting of hydrogen, alkylhaving from 1 to 6 carbon atoms, alkenyl from 3 to 5 carbon atoms,alkynyl having from 3 to 5 carbon atoms, hydroxy substituted alkylhaving from 2 to 5 carbon atoms, cycloalkyl having from 3 to 8 carbonatons, --(CH₂)_(q) C₆ H₄ R⁸ and --(CH₂)_(q) C₁₀ H₆ R⁸ where q is 0 or 1;

R⁴ is a member selected from the group consisting of hydrogen, alkylhaving from 1 to 6 carbon atoms, alkenyl having from 3 to 5 carbonatoms, cycloalkyl and cycloalkylmethyl wherein said cycloalkyl has from3 to 8 carbon atoms, ##STR11## R¹⁰, CH₂ R¹⁰ and (CH₂)_(q) C₆ H₄ R⁸ whereA is S or O, q as defined above and R¹⁰ is a member selected from thegroup consisting of ##STR12## where r is 1 or 2;

R⁵ is a member selected from the group consisting of alkyl having from 1to 7 carbon atoms, alkenyl having 3 to 5 carbon atoms, cycloalkyl havingfrom 3 to 8 carbon atoms, hydroxy substituted alkyl having from 2 to 5carbon atoms, CH₂ C₆ H₄ R⁸, CH₂ C₁₀ H₆ R⁸, CH₂ R¹⁰ and CH₂ O-pyridyl;

R⁶ is a member selected from the group consisting of hydrogen, C₆ H₄ R⁸,--(CH₂)_(p) ZR¹⁵, alkyl having from 1 to 6 carbon atoms, and said alkylsubstituted by a member selected from the group consisting of Cl, F, Br,OH, CH₃ O, SO₂ CH₃ and NHSO₂ CH₃, where p and A are as previouslydefined and Z is a member selected from the group consisting of O, S,SO, SO₂, NH and NR¹⁶ ;

R⁷ is a member selected from the group consisting of alkyl having fromone to six carbon atoms, hydroxyalkyl having from one to five carbonatoms, --(CH₂)_(q) C₆ H₄ R⁸ and COC₆ H₄ R⁸ ;

R⁸ is a member selected from the group consisting of H, Cl, Br, F, CH₃,CH₃ O, CF₃, OH, SO₂ CH₃ and NHSO₂ CH₃ ;

R⁹ is a member selected from the group consisting of H, Cl, CH₃, C₂ H₅and phenyl;

R¹¹ is hydrogen or methylthio and

R¹² is a member selected from the group consisting of H, NH₂ alkylhaving from one to four carbon atoms and NHCO₂ R¹⁴ ;

R¹⁴ is alkyl having from one to four carbon atoms;

R¹⁵ is a member selected from the group consisting of alkyl having fromone to four carbon atoms, C₆ H₄ R⁸ and C₁₀ H₆ R⁸ ; and R¹⁶ is hydrogenor alkyl having from one to four carbon atoms.

Preferred compounds of the invention include the compounds of formula(I) wherein Y¹, Y² and Y³ are as defined above and NR¹ R² is ##STR13##where R⁴ is a member selected from the group consisting of ##STR14## andcycloalkyl having from 3 to 8 carbon atoms and A, r and R¹¹ are aspreviously defined. Also preferred are the compounds of formula (I)wherein Y¹, Y² and Y³ are as defined above and NR¹ R² is ##STR15## whereR⁵ is hydroxy substituted alkyl having from 2 to 5 carbon atoms.

Particularly preferred compounds of the invention are:

2-[4-(2-furoyl)piperazin-1-yl]-4-amino-7,8-dimethoxyquinazoline,

2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6-chloro-7-methoxyquinazoline,

2-[4-(2-furoyl)piperazin-1-yl]-4-amino-6-chloro-7,8-dimethoxyquinazoline,

2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-yl]-4-amino-7,8-dimethoxyquinazoline,

2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-yl]-4-amino-6-chloro-7-methoxyquinazolineand

2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-yl]-4-amino-6-chloro-7,8-dimethoxyquinazoline,and their hydrochloride salts.

The invention further provides certain intermediates useful in thepreparation of the compounds of formula (I). These intermediates are ofthe formula ##STR16## where Y¹, Y² and Y³ are as defined above.

The term "pharmaceutically acceptable" used herein to describe an acidaddition salt of a compound of formula (I) refers to those salts havinganionic species of a variety of relatively non-toxic inorganic ororganic acids. The anion does not contribute appreciably to the toxicityof the salt or to its pharmacological activity. Illustrative of suchsalts are those formed with acetic, lactic, succinic, maleic, tartaric,citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric,phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonicacids such as methanesulfonic, benzenesulfonic, p-toluenesulfonic, andrelated acids. Preparation of the mono-acid addition salts may becarried out in conventional manner by treating a solution or suspensionof the free base in a reaction inert organic solvent with one chemicalequivalent of the acid or if the di-acid addition salt is desired, atleast two chemical equivalents of the acid. Conventional concentrationor crystallization techniques are employed in isolating the salts.

The compounds of formula (I) are especially useful as antihypertensiveagents having significant advantages over the prior art. The Y¹substituent, at the 6-position of the invention compounds, is eitherhydrogen or chloro, groups which are not prone to metabolic attack.Consequently, the invention compounds are not subject to facilemetabolic demethylation with resultant loss of activity, as has beenshown for prazosin. Accordingly, the compounds of formula (I) havegreater duration of action than prazosin and other 6,7-dimethoxy- and6,7,8-trimethoxyquinazoline antihypertensive agents known in the art.

The invention compounds also have significantly greater water solubilitythan prazosin and as a result of their improved solubility, areuniformly absorbed by all patients. Furthermore, they can beadministered in time release form, as well as parenterally, includingintraveneously.

DETAILED DESCRIPTION OF THE INVENTION

The antihypertensive compounds of the invention are represented byeither of the formulae ##STR17## wherein Y¹, Y², Y³, R, R¹ and R² are aspreviously defined. They are prepared by synthetic methods describedbelow.

Scheme I, below, outlines a preferred reaction sequence. In the firststep a 4-alkoxyanthranilic acid of formula (IX) containing the desiredsubstituents Y¹ and Y³ as defined above is cyclized to the corresponding2,4-dioxoquinazoline of formula (X). The cyclization is brought about byreacting the compound (IX) with sodium or potassium cyanate or ureaaccording to the procedure of Curd et al., Jour. Chem. Soc., 777 (1947)for the corresponding 6,7-dimethoxyquinazolinediones. Of course, as willbe apparent to one skilled in the art, the anthranilic acids of formula(IX) may be replaced in this reaction by the corresponding compounds inwhich the carboxylic acid moiety is replaced by a CONH₂, CN, orcarboxylic ester group with satisfactory results. The cyclized compoundsof formula (X) are novel compounds, of value as intermediates forpreparing the antihypertensive compounds of the invention. As will berecognized by one skilled in the art, they may also be represented asthe corresponding tautomeric 2,4-dihydroxyquinazolines. ##STR18##

In preparing the intermediates of formula (X), the starting material(IX) is suspended in a polar solvent in the presence of acid, preferablywater-acetic acid, and a 2-4 molar excess of the cyanate salt, e.g.,potassium cyanate or urea added. The resulting mixture is then heated ata temperature of from about room temperature up to the refluxtemperature of the solvent until reaction is substantially complete.Typical reaction times are from about 1 to 24 hours. The mixture is thencooled, made alkaline with sodium hydroxide or potassium hydroxide andthe alkaline mixture heated again at a temperature of from about 70° to100° C. for 1 to 5 hours. The resulting sodium salt of the product (X)is then acidified and isolated by standard methods known in the art.

The intermediate of formula (X) is then reacted with a mixture ofphosphorous pentachloride and phosphorous oxychloride or thecorresponding phosphorous bromides to prepare the corresponding2,4-dihaloquinazolines. The preferred embodiment, in which the abovephosphorous chlorides are employed, is depicted in Scheme I to providethe intermediates of formula (XI) in which R, Y¹ and Y³ are as definedabove. Typically the dione (X) and a 2 to 4 molar excess each ofphosphorous pentachloride and phosphorous oxychloride are heated atreflux for 2 to 6 hours, the residual phosphorous oxychloride evaporatedand the residue slurried in a reaction inert organic solvent, forexample, chloroform or dichoromethane, and poured into ice-water.Insoluble material is removed and the product isolated from the organiclayer by evaporation or precipitation by addition of a non-solvent, forexample, hexane, to precipitate the dichloro compound of formula (XI).

The key 2-chloro-4-aminoquinazoline intermediates of formula (XII) areprovided by reacting equimolar amounts of ammonia and2,4-dichloroquinazoline (XI) in the presence of a reaction inert organicsolvent. Examples of suitable reaction inert solvents are ethyl ether,tetrahydrofuran, chloroform and benzene. A preferred solvent istetrahydrofuran. In ordinary practice a preferred excess of ammonia offrom one to ten moles would be used in order to shift the reactiontoward completion. The temperature at which this reaction can be carriedout is from about 25° to 200° C. for a period of from one to 48 hours. Apreferred reaction temperature and time for this reaction would be about25° to 60° C. for about five hours. Upon completion of the reaction theproduct is recovered by conventional means. For instance, the solventcan be evaporated and the crude solid can be triturated with water orprecipitated from dilute aqueous acid in crystalline form andsubsequently recrystallized from any number of organic solvents such asmethanol, dimethylformamide or their mixtures with water.

Conversion of the 2-chloroquinazoline intermediate of formula (XII) tothe desired compound of formula (III) is accomplished by contacting theintermediate (XII) with an equimolar amount of an amine of the formulaR¹ R² NH in the presence of an aqueous or an organic solvent. A smallmolar excess of amine is generally employed. Preferred organic solventsfor this reaction include polar solvents like tetrahydrofuran, dioxane,dimethylacetamide, dimethylformamide; alcohols such as methanol, ethanoland isoamyl alcohol and ketones such as methylethylketone andmethylisobutylketone. Particularly preferred solvents are isoamylalcohol and methylisobutylketone. The reaction mixture is heatedpreferably at a temperature of from about 60° to 160° C. for from one to65 hours. Particularly preferred reaction temperatures are from about100° to 140° C. and temperatures in this range are conveniently obtainedby maintaining the reaction mixture at the reflux temperature of theparticularly preferred solvents. At such temperature the reaction isordinarily complete in from about two hours to two days.

Alternate procedures for preparing the compounds of the invention mayalso be used with satisfactory results. For example, the alternatemethods disclosed in U.S. Pat. No. 3,511,836 for preparation of prazosinand its analogs can also be used with the appropriate starting materialsto provide the invention compounds of formula (I). These methods areenumerated and discussed briefly below.

1. 2-Amino-4-chloroquinazolines (XXIX) prepared by methods analogous tothose described in U.S. Pat. No. 3,511,836 for the corresponding6,7-dialkoxy- compounds may be reacted with ammonia under conditionsdescribed above for the conversion of compounds (XI) to (XII) withresultant formation of the desired product of formula (I) where Y¹, Y²,Y³, R¹ and R² are as defined above. ##STR19##

2. The quinazolinedione of formula (X) can be reacted with a reagentsuch as phosphorous pentasulfide or the like to form the corresponding2,4-quinazolinedithione which are in turn reacted with an alkyl orbenzyl halide to form the corresponding 2,4-dithioalkylquinazoline or2,4-dithiobenzylquinazoline. This is then reacted with ammonia by theprocedure previously described for the reaction of the2,4-dichloroquinazolines (XI) to provide the corresponding4-amino-2-thioalkyl (or thiobenzyl) quinazoline (XX). The lattercompound is then converted to the desired compound (I) by employingconditions previously described for the formation of compound (I) from2-chloro compounds of formula (XII). ##STR20## where Y¹, Y², Y³, R¹ andR² are as previously defined.

3. Compounds of formula (I) wherein NR¹ R² forms a heterocyclic moietyof the formula ##STR21## where X² is NR³, NCOR⁴ or NCOOR⁵ and m, n, R³,R⁴ and R⁵ are as previously defined, but R³ is other than hydrogen, canalso be prepared from the compound wherein X² is NH, for example NR¹ R₂is piperazino, by acylation, alkylation or carbonyloxylation. ##STR22##The compound (XXI) is reacted with a compound of formula R³ --X³, R⁴COX³ or X³ COOR⁵, where R³, R⁴ and R⁵ are as defined above and X³ is aleaving group, preferably the halides, Cl or Br. When the preferredhalides are employed it is advantageous to use at least a slight molarexcess to ensure complete reaction. The intermediate (XXI) and reagentof formula R³ X³, R⁴ COX³ or X³ COOR⁵ are contacted in the presence of areaction inert organic solvent, for example, benzene, tetrahydrofuran,acetone methylethyl ketone, methylisobutyl ketone, 1,2-dimethoxyethaneor diethyleneglycol dimethylether. A preferred such solvent ismethylisobutyl ketone. The reaction may be carried out successfully overa wide range of temperatures. However, a temperature in the range ofabout 0° C. up to the reflux temperature of the solvent is preferred forreasons of efficiency and convenience. At such a preferred temperaturethe reaction is ordinarily complete in from about 30 minutes to sixhours. The resulting solid product is then isolated as either thehydrohalide or the free base by conventional methods and purified, ifdesired, by crystallization, column chromatography or the like.

4. In this method the 2-aminobenzonitrile intermediate of formula (XIV)is reacted with a guanidine of the formula ##STR23## where R¹ and R² areas defined above. The benzonitrile (XIV) and an equivalent amount, butpreferably a molar excess, of the guanidine are contacted in thepresence of a reaction inert organic solvent, for example, ethyleneglycol, diethyleneglycol, dimethylformamide, dimethylsulfoxide ordiethyleneglycol dimethylether, at a temperature of from about 120°-180°C. for from about four to 15 hours. The desired product of formula (I)is then isolated by well known methods, for example, the solvent isevaporated, the residue contacted with water and the precipitatedproduct is filtered, recrystallized and dried. The reaction isillustrated as follows: ##STR24##

The guanidine starting materials are prepared by methods well known inthe art. For example, the amine of formula R¹ R² NH is reacted withcyanogen bromide to form the corresponding N-cyano-compound which, inturn, is reacted with hydroxylamine, followed by catalytic hydrogenationusing the methods and conditions of Carrington, Jour. Chem. Soc.,London, 2527 (1955) for the conversion of anthranilonitrile into2-aminobenzamidine.

Variations of the above method can also be carried out employing eitherof the following starting materials in place of the 2-aminobenzonitrile(XIV). ##STR25## The 2-chlorobenzonitriles are obtained, for example, bydiazotization of (XIV) in the presence of cuprous chloride. The2-aminobenzamidines are obtained, for example, by the method ofCarrington, above.

5. 2-Chloro-4-alkoxy-7,8-disubstituted quinazolines, which are preparedby methods described by Curd et al., Jour. Chem. Soc., 775 (1974) forthe isomeric 2-chloro-4-alkoxy-6,7-disubstituted quinazolines, can bereacted with an amine, R¹ R² NH, to obtain the corresponding2-aminoquinazolines. The 4-alkoxy substituent is then replaced by NH₂ byreaction with ammonia as described above for the 4-chloro compounds offormula (XXIX). This reaction sequence is exemplified below for a2-chloro-4-ethoxyquinazoline starting material. ##STR26## Y¹, Y², Y³, R¹and R² are as previously defined. The 4-thioalkylquinazolinescorresponding to the above 4-alkoxy compounds can also be employed asstarting materials in this sequence.

6. The compounds of the invention are also provided by methods disclosedin U.S. Pat. No. 3,935,213 for prazosin, trimazosin and analogs thereofas set forth below where Y¹, Y², Y³, R¹ and R² are as previouslydefined; ##STR27## A¹ is selected from the group consisting of CN andC(═NH)XR₃ wherein X is O or S and R₃ is alkyl having from one to sixcarbon atoms; and Q is CN or --C(═NH)NH₂. Preferably the reaction iscarried out in the presence of from about 0.5 to 5 molar equivalents ofa basic catalyst, e.g., sodium hydride, potassium ethoxide ortriethylamine, and at a temperature in the range of from about 50° to180° C. The products of formula (I) are isolated by well known methods,for example, those described in U.S. Pat. No. 3,935,213.

7. Compounds of formula (I) are also obtained by employing theappropriate starting material of formula (XIV) in the process describedin Belgian Pat. Nos. 861,821 and 861,822 for synthesis of prazosin. Themethod is outlined in Scheme II. The o-aminobenzonitrile (XIV) whereinY¹, Y² and Y³ are as defined above is reacted with at least an equimolaramount of thiophosgene in a reaction inert organic solvent, e.g.,1,2-dichloroethane. ##STR28## To the mixture is added a base, e.g.calcium carbonate, water and the mixture stirred typically at about0°-5° C., then warmed to about room temperature until reaction issubstantially complete. The o-isothiocyanatobenzonitrile (XV) producedis isolated in crude form for use in the next step. The intermediate(XV), dissolved in a reaction inert organic solvent, typically ethylacetate, is contacted with the amine of formula R¹ R² NH, where R¹ andR² are as defined above, at a temperature below 0° C., preferably atabout -30° to -5° C. to obtain the o-thioureidobenzonitrile (XVI). Thisis then contacted with a methylating agent, for example methyl iodide ormethyl bromide, and the resulting S-methyl hydrohalide salt treated witha mild base to obtain the S-methylthioformamidate of formula (XVII)which is cyclized by reaction with anhydrous ammonia in the presence ofa polar solvent and an alkali metal amide to provide the desiredcompounds of formula (I). Preferred polar solvents for the cyclizationare formamide or N,N-dimethylformamide. Also preferred for the finalstep are use of from 1 to 3 equivalents of alkali metal amide,especially sodium amide and a temperature of from about 100° to 150° C.

8. In U.S. Pat. No. 4,138,561 a novel process for preparing prazosin andtrimazosin is disclosed. This method is also suitable for preparation ofthe compounds of the present invention as shown below. ##STR29##

The starting materials of formula (XXXIII) wherein Y¹, Y² and Y³ are aspreviously defined are known compounds [see, for example, Gibson et al.,J. Chem. Soc., 111, 79 (1917); Munavalli et al., Bull. Soc. Chim.,France, 3311 (1966); Chem. Abstr., 66, 46303s (1967); and GermanOffenlegungsschrift 1,959,577; Chem. Abstr., 75, 63397d (1971)]. Thestarting material (XXXIII) is converted to the isothiocyanate (XXXIV) asdescribed above for intermediate (XV) and this is reacted with an amineR¹ R² NH wherein R¹ and R² are as defined above to provide thesubstituted thiourea (XXXV) by the method described above forintermediate (XVI). The intermediate (XXXV), in turn, is reacted with analkylating agent, Y⁴ X⁴ to obtain an intermediate of formula (XXXVI) inwhich Y⁴ is alkyl having from one to four carbon atoms or an arylderivative containing electron withdrawing groups, for example,2,4-dinitrophenyl, and X⁴ is a member selected from the group Cl, Br, I,alkyl-SO₄ having from one to four carbon atoms, C₆ H₅ SO₂, F₃ CSO₂ andFSO₃. An especially preferred alkylating agent, Y⁴ X⁴, is methyl iodide.Alternatively, as disclosed in U.S. Pat. No. 4,138,561, phosgene may beused in the first step in the above reaction sequence of Scheme III,wherein each of the intermediates (XXXIV) to (XXXVI) is thecorresponding compound in which an atom of oxygen replaces the sulfuratom shown therein. The intermediate of formula (XXXVI) is then reactedwith cyanamide to provide the corresponding carboxamidine intermediateof formula (XXXVII).

Alkylation of thiourea derivatives (XXXV) and subsequent reaction withcyanamide is normally carried out in a reaction inert organic solvent.Suitable solvents include dioxane, tetrahydrofuran, dimethyl sulfoxide,and the alkanols having from one to five carbon atoms. These reactionsare preferably carried out at a temperature of from about 25° to 100° C.for a period of about 0.5 to 24 hours. The intermediate of formula(XXXVII) may also be obtained by alternate procedures described in U.S.Pat. No. 4,138,561.

The conversion of carboxamidine intermediates (XXXVII) to the desiredquinazolines of formula (I) is carried out by reaction with cyclizingreagents such as phosphorus trichloride or phosphorus pentachloride in asolvent amount of phosphorus oxychloride. Other phosphorus halides andphosphorous oxyhalides such as phosphorus tribromide and phosphoruspentabromide in a solvent amount of phosphorus oxybromide may beemployed. The ring closure may also be carried out by reacting theintermediate (XXXVII) with acidic reagents such as aqueous hydrogenchloride, hydrogen chloride in phosphorus oxychloride, trichloroaceticacid or Lewis acid catalysts such as ZnCl₂, FeCl₃, AlCl₃, AlBr₃, and thelike.

With respect to carrying out the reaction with phosphorus halides,approximately equimolar amounts of the carboxamidine (XXXVII) andphosphorus halides are employed with a convenient amount of phosphorusoxyhalide relative to the amount of starting material (XXXVII). The term"solvent amount" as used herein refers to a quantity of phosphorusoxychloride or phosphorous oxybromide sufficient to provide good mixingand handling characteristics with respect to the reaction mixtures. Forthis purpose a ratio of from about 2 to 15 ml. of the phosphorusoxyhalide for each gram of carboxamidine reactant of formula (XXXVII) isgenerally preferred.

Commonly used temperatures for carrying out the cyclization reactionrange from about 25° to 125° C. with a preferred temperature of fromabout 70° to 100° C. As will be appreciated by those skilled in the art,reaction times and conditions required for cyclization of intermediates(XXXVII) to form the desired products of formula (I) vary according toseveral factors such as temperature and reaction time. For example, atlower temperatures, longer reaction periods are needed, while at highertemperatures, the cyclization reaction is completed in a shorter time.Reaction periods of from about 0.5 to 24 hours can be used, however aperiod of from about 1 to 3 hours is preferred at the above mentionedpreferred reaction temperatures.

The required starting materials of formula (IX) for the procedure ofScheme I, above are obtained by the reaction sequences illustrated inSchemes IV, V and VI below, for the case where R is CH₃. ##STR30##

In the reaction schemes above and below, for the sake of convenience,the lower case letters a, b and c are used after the Roman numerals forthe compounds shown to denote the following:

a. Y¹ =H, Y² =Y³ =OR where R is alkyl having from one to three carbonatoms.

b. Y¹ =Cl, Y² =Y³ =OR, R is as defined above.

c. Y¹ =Cl, Y² =OR as defined above, Y³ =H. ##STR31##

In the reaction sequence of Scheme IV vanillin is acetylated with, forexample acetic anhydride or acetyl chloride by well known methods andthe acetylated intermediate nitrated to obtain4-acetoxy-3-methoxy-2-nitrobenzaldehyde (V). The acetyl group is removedby hydrolysis, for example by treatment with an aqueous strong base suchas sodium hydroxide, followed by acidification to provide the4-hydroxy-3-methoxy-2-nitrobenzaldehyde intermediate of formula (VI).This intermediate is then alkylated with one of the well knownalkylating agents commonly employed for the conversion of phenolicgroups to the corresponding alkyl ethers. Examples of such alkylatingagents are dimethylsulfate, diethyl sulfate, methyl bromide, n-propyliodide and ethyl iodide. In the case illustrated in Scheme IV amethylating agent is employed to provide3,4-dimethoxy-2-nitrobenzaldehyde, (VII). Compounds in which the twoether groups are different are obtained by use of, for example, diethylsulfate or n-propyl iodide as the alkylating agent. When ethyl vanillinor n-propyl vanillin are employed in place of vanillin as startingmaterial in this reaction sequence the corresponding compounds arelikewise obtained wherein the corresponding alkoxy groups are4,5-diethoxy, 4,5-dipropoxy, 4-ethoxy-5-methoxy, 4-ethoxy-5-n-propoxy,4-n-proproxy-5-methoxy and 4-n-propoxy-5-ethoxy.

The dialkoxy intermediate of formula VII, e.g., is then oxidized to thecorresponding carboxylic acid. While a wide variety of oxidizing agentsand conditions are known in the art to bring about oxidation of aromaticaldehydes to the corresponding carboxylic acids, preferred oxidizingconditions are those employing potassium permanganate in aqueous acetoneat the reflux temperature of the mixture. The2-nitro-4,5-dialkoxy-benzoic acid intermediate, e.g. the compound offormula (VIII) is isolated by known means and reduced to thecorresponding 2-amino acid, for example, the compound of formula (IXa,R=CH₃), by well known means, e.g. by catalytic hydrogenation employing anoble metal hydrogenation catalyst. A preferred catalyst is palladium.

The intermediate of formula (IXa) is useful as a starting material inthe reaction sequence shown in Scheme I, above, to provide thecorresponding invention compounds of formula (Ia) or (IIIa).Alternatively, as shown in Scheme IV, the intermediates (IXa) serve as astarting material for the corresponding 5-chloro intermediates offormula (IXb). The carboxylic acid is first esterified to form an alkylester, e.g. the methyl or ethyl ester, by well known means. The ester isthen chlorinated employing, for example chlorine or sulfuryl chlorideand the latter reagent is preferred for reasons of efficiency and easeof handling. Typically a slight molar excess, e.g. a 20% molar excess,of sulfuryl chloride is added to a cooled solution of the intermediatecarboxylate ester of the acid (IXa) in a chlorinated hydrocarbonsolvent, e.g. chloroform, methylene chloride or 1,2-dichloroethane, theresulting mixture is allowed to warm to room temperature, then heated atreflux until reaction is substantially complete, e.g. from one hour to24 hours. The crude 5-chloro ester is then hydrolyzed, e.g. by means ofsodium hydroxide as described above to provide the corresponding5-chloro acid of formula (IXb).

The starting 5-chloro-5-alkoxyanthranilic acids of formula (IXc) areobtained as shown in Scheme V. 4-Methoxy-2-nitroaniline (XVIII) istreated with sodium nitrite in concentrated hydrochloric acid underconditions well known to those skilled in the art, to form anintermediate diazonium salt to which is then added an aqueous solutioncontaining an equimolar amount of cuprous cyanide and a molar excess,typically a 50% excess, of potassium cyanide while warming the reactionmixture on a steam bath. The product 4-cyano-3-nitroanisole (XIX) isthen isolated and then hydrolyzed, e.g. in the presence of aqueoussulfuric or hydrochloric acid to obtain the carboxylic acid of formula(XXI). This, in turn, is hydrogenated as described above for theconversion of compound (VIII) to (IXa) to provide 4-methoxy anthranilicacid (XXII) and the latter chlorinated to provide the desired compound(IXc, R=CH₃) employing the conditions described above for the conversionof compounds of formula (IXa) to 5-chloro compounds (IXb).

As shown in Scheme V, other synthetic routes may be employed to providethe desired starting material of formula (IXc). In one such alternatemethod the 4-cyano-3-nitroanisole (XIX) is hydrogenated as previouslydefined for conversion of compound (VIII) to compound (IXa) to providethe aminonitrile of formula (XX). This is chlorinated as described abovefor the conversion of compounds (IXa) to (IXb) and the resulting5-chloro nitrile (XIVc, R=CH₃) is hydrolyzed as described for thepreparation of compound (XXI) from nitrile (XIX), to provide the desiredcompound (IXc, R=CH₃).

Another route shown in Scheme V involves oxidation of the startingmaterial 4-methyl-3-nitroanisole with potassium permanganate to providethe intermediate (XXI) which is converted to compound (IXc) aspreviously described.

As will be obvious to those skilled in the art when the methoxy grouppresent in the starting materials of formula (XVIII) and (XXIII)employed in Scheme V is replaced by an ethoxy or n-propoxy group, thecorresponding compounds of formula (IXc) are obtained wherein R is C₂ H₅or n-C₃ H₇, respectively.

Similarly, replacement of either one or both of the methoxy groupspresent in the starting material of formula (XXV) employed in Scheme VIby ethoxy or n-propoxy provides the corresponding compounds of formula(IXa) or (IXb).

The starting materials of formula (XIV) employed in the reactionsequence illustrated in Scheme II for the preparation of the compoundsof the invention, are prepared as shown in Scheme V for compounds (XIVc)and in Scheme VI for compounds (XIVa) and (XIVb), and as describedabove.

Many of the requisite amines of formula R¹ R² NH wherein R¹ and R² areas previously defined are known compounds, see for example, thereferences mentioned above as prior art. Those that are new are preparedby methods which will be apparent to those skilled in the art. Forexample, the amines of formula ##STR32## where a is 1, 2, or 3, n is 2,or 3 and R⁶ is as defined above are obtained by reacting the appropriatecorresponding N-protected amine wherein R⁶ is hydrogen with, forexample, a compound of the formula (R₆)'--Hal where (R⁶)' has any of thevalues assigned above for R⁶ except hydrogen and Hal is Cl, Br, I orother known leaving groups such as SO₃ CH₃. The reaction is typicallycarried out employing an equimolar amount of a metal hydride, forexample sodium hydride and in the presence of a reaction inert organicsolvent, e.g. dimethylformamide. The N-protecting group is then removedto provide the desired amine of the above formula. Typically, protectinggroups such as acetyl or benzyl are employed. The former being removedby hydrolysis and the latter by catalytic hydrogenation, e.g., employinga palladium catalyst.

Alternatively, the above compounds wherein R⁶ contains an ether moietycan be obtained by the reaction sequence below which illustrates thepreparation of 4-(ethoxy-n-propoxy)piperidine. ##STR33##

Many of the requisite amines of formula ##STR34## wherein a, n and R⁷are as defined above are known compounds. Those that are not known areprepared by well known methods. For example, the R⁷ -substitutedpiperidines may be obtained by catalytic hydrogenation of thecorresponding R⁷ -substituted pyridines. The cyclic amines of the aboveformula wherein R⁷ is alkyl having from one to six carbon atoms areprovided by reacting the appropriate N-protected aminoketone with analkyl Grignard reagent, for example, as outlined below. ##STR35## Thecatalytic hydrogenolysis of the tertiary hydroxy group is oftenfacilitated by prior acetylation.

The desired cyclic amines wherein R⁷ is hydroxyalkyl having from two tofive carbon atoms are obtained, for example by methods outlined below.##STR36## The compounds of formula (XXXVIII) wherein R⁷ is hydroxymethylare obtained by e.g. lithium aluminum hydride reduction of thecorresponding aldehydes or carboxylic acid esters.

The compounds of formula (XXXVIII) wherein R⁷ is R⁸ C₆ H₄ (CH₂)₈ whereinq is 0 or 1 and R⁸ is as previously defined may also be obtained via aGrignard reaction as shown below, for example. ##STR37##

The starting materials of formula (XXXVIII) wherein R⁷ is R⁸ C₆ H₄ COmay be obtained, for example, by Friedel-Crafts acylation of R⁸ C₆ H₅ byan N-protected carboxylic acid halide as illustrated below. ##STR38##The piperidine derivatives of the latter formula are also obtained byemploying the corresponding pyridine carboxylic acid halides andcompound of formula R⁸ C₆ H₅ in the Friedel-Crafts acylation followed byhydrogenation of the pyridine moiety.

The cyclic aminocarboxylic acid precursors of the above N-protectedcyclic aminoacid halides are either readily available or may be obtainedby the well known Dieckmann reaction followed by hydrolysis anddecarboxylation of the resulting alpha-keto-ester to provide a cyclicketone intermediate which can be converted to the desired carboxylicacid by a variety of methods, e.g. ##STR39##

In the above reaction sequence a and n are as defined above and R₁₃ is asuitable amino protecting group, e.g. benzyl or acetyl. As will berecognized by one skilled in the art, in the above reaction sequencewhen R₁₃ is benzyl the ketone reduction step is preferably carried outby a metal hydride, e.g. sodium borohydride or lithium aluminum hydride,and removal of the benzyl group is accomplished by hydrogenolysis.

Use of a longer chain R₁₃ -protected iminodicarboxylate esters in theabove Dieckmann reaction can be employed to provide the correspondingR₁₃ -protected amino ketones of the formula ##STR40## which uponWolff-Kishner reduction and deprotection provides starting materials offormula ##STR41## where a, n and p are as defined above.

The antihypertensive activity of the compounds of the invention is shownby their ability to lower the blood pressure of conscious spontaneouslyhypertensive rats and conscious renally hypertensive dogs, whenadministered orally at doses of up to 30 mg./kg.

For instance,2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-yl]-4-amino-6-chloro-7,8-dimethoxyquinazoline,a typical and preferred compound of the invention, has been found tolower blood pressure in renally hypertensive dogs to a statisticallysignificant degree, e.g., when this compound is administered orally atdoses as low as 0.2 mg./kg., it effected a decrease of 30 mm. Hg after 4hours with no significant change in heart rate or other side effect.Similarly, at the same dosage2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-yl]-4-amino-6-chloro-7-methoxyquinazoline,a particularly preferred compound of the invention, caused a reductionof 40 mm. Hg after one hour which increased only by 20 mm. Hg 6 hoursafter administration; and another particularly preferred compound:2-[4-(2-furoyl)-1-piperazinyl]-4-amino-6-chloro-7-methoxyquinazolineeffected a reduction in blood pressure of 40 mm. Hg which increased byonly 5 mm. Hg six hours after the oral dose (0.2 mg./hg.) had beenadministered. Again, no significant heart rate change or other unwantedside effect was noted with the latter two compounds.

In addition to their useful antihypertensive activity, the compounds ofthe invention also demonstrate activity in standard tests designed toshow vasodilator activity, antiglaucoma activity and utility in thetreatment of congestive heart failure.

The compounds of the invention can be administered alone, but willgenerally be administered in admixture with a pharmaceutical carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, they can be administeredorally in the form of tablets containing such excipients as starch orlactose, or in capsules either alone or in admixture with excipients, orin the form of elixirs or suspensions containing flavoring or coloringagents. They can be injected parenterally, for example, intramuscularly,intravenously or subcutaneously. For parenteral administration, they arebest used in the form of a sterile aqueous solution which can containother solutes, for example, enough salt or glucose to make the solutionisotonic. For treatment of glaucoma, they can be administered topicallyas well as by the above mentioned routes of administration. For topicalapplication, a compound of the invention is admixed under sterileconditions with a pharmaceutically-acceptable liquid carrier or solventsuch as water, a glycol or mixtures thereof, and toxicity adjustors,preservatives and buffers added as required. The resulting solution ordispersion is then sterilely filtered and used to fill sterile bottles.

The invention also provides a pharmaceutical composition comprising anantihypertensive effective amount of a compound of the formula (I) orpharmaceutically acceptable acid addition salts thereof together with apharmaceutically acceptable diluent or carrier.

The compounds of the invention can be administered to humans for thetreatment of hypertension or congestive heart failure by either the oralor parenteral routes, and may be administered orally at dosage levelsapproximately within the range 1 to 500 mg./day for an average adultpatient (70 kg.), given in a single dose or up to 3 divided doses.Intravenous dosage levels would be expected to be about one-half toone-tenth of the daily oral dose. Thus for an average adult patient,individual oral doses in the tablet or capsule form will beapproximately in the range from 0.5 to 250 mg. of the active compound.Variations will necessarily occur depending on the weight and conditionof the subject being treated and the particular route of administrationchosen as will be known to those skilled in the art.

The invention yet further provides a method of treating an animal,including a human being, having hypertension, which comprisesadministering to the animal an antihypertensive effective amount of acompound of the formula (I) or pharmaceutically acceptable acid additionsalt thereof or pharmaceutical composition as defined above.

The following Examples illustrate the invention.

EXAMPLE 1 7,8-Dimethoxyquinazoline-2,4-dione (Xa)

Acetic acid (177.4 ml., 3.1 moles) was added to a vigorously stirredsuspension of 3,4-dimethoxyanthranilic acid (436.5 g., 2.21 moles) in 10liters of water. Then 2.24 liters of 20% potassium cyanate (5.53 moles)solution was gradually added and the mixture was stirred for one hour at40° C. After cooling the reaction mixture to 20° C., 3.54 kg. sodiumhydroxide pellets were added maintaining the temperature below 40° C.The reaction mixture was heated to 90° C. for 45 minutes and then slowlycooled in an ice bath. The sodium salt of the product was filtered,resuspended in 6 liters of water, acidified with concentratedhydrochloric acid (370 ml.), cooled and filtered to yield 404 grams(82%) of the product. Recrystallization from dimethylformamide gavecolorless crystals, M.P. 314°-6° C.

Analysis, Percent Calcd. for C₁₀ H₁₀ N₂ O₄ : C, 54.05; H, 4.54; N,12.61. Found: C, 53.96; H, 4.57; N, 12.63.

EXAMPLE 2 2,4-Dichloro-7,8-dimethoxyquinazoline (XIa)

A mixture of 7,8-dimethoxyquinazoline-2,4-dione (400 g., 1.80 moles),phosphorous pentachloride (750 g., 3.60 moles) and phosphorousoxychloride (4 liters) was refluxed under nitrogen for three hours.Phosphorus oxychloride (POCl₃) was removed in vacuo and residual POCl₃was removed as an azeotrope with toluene. The solid residue was slurriedin eight liters of dichloromethane and the slurry slowly added toice-cold H₂ O. The suspension was stirred and unreacted startingmaterial (54.0 g.) was filtered off. The organic layer was separated,dried over sodium sulfate and filtered. The solution was concentratedand then 4 liters of hexane was slowly added. Upon cooling, a paleyellow product (346 g., 80.4%) was collected by filtration andrecrystallized from toluene/ether, M.P. 153°-5° C.

Analysis, Percent Calcd. for C₁₀ H₈ Cl₂ N₂ O₂ : C, 46.35; H, 3.11; N,10.81. Found: C, 46.14; H, 3.33; N, 10.60.

EXAMPLE 3 2-Chloro-4-amino-7,8-dimethoxyquinazoline (XIIa)

Ammonia was passed into a solution of2,4-dichloro-7,8-dimethoxyquinazoline (287 g., 1.11 moles) intetrahydrofuran (6 liters) for five hours at room temperature. Afterstirring an additional hour the suspension was concentrated in vacuo to2 liters and filtered. The solid was suspended in 2 liters of water,filtered, washed with water and cold methanol. Recrystallization fromdimethylformamide/water yielded 164 g. (62%) of pure product, M.P. 300°.(dec.).

Analysis, Percent Calcd. for C₁₀ H₁₀ ClN₃ O₂ : C, 50.11; H, 4.21; N,17.53. Found: C, 50.07; H, 4.24; N, 17.58.

EXAMPLE 3A

When the appropriate starting material selected from those provided inPreparation I are employed in place of 3,4-dimethoxyanthranilic acid inthe procedure of Example 1 and in each case the resulting productcarried thorough the procedures of Examples 2 and 3, the followingcompounds are provided in a like manner.

    ______________________________________                                         ##STR42##                                                                           Y.sup.2       Y.sup.3                                                  ______________________________________                                               C.sub.2 H.sub.5 O                                                                           C.sub.2 H.sub.5 O                                               n-C.sub.3 H.sub.7 O                                                                         n-C.sub.3 H.sub.7 O                                             CH.sub.3 O    C.sub.2 H.sub.5 O                                               n-C.sub.3 H.sub.7 O                                                                         CH.sub.3 O                                                      C.sub.2 H.sub.5 O                                                                           CH.sub.3 O                                                      n-C.sub.3 H.sub.7 O                                                                         C.sub.2 H.sub.5 O                                        ______________________________________                                    

EXAMPLE 42-[4-(2-Furoyl)piperazine-1-yl]-4-amino-7,8-dimethoxyquinazolinehydrochloride

A mixture of 2-chloro-4-amino-7,8-dimethoxyquinazoline (3.00 g., 12.5mmoles) and 1-(2-furoyl)piperazine (2.71 g., 15.0 mmoles) was refluxedin 80 ml. isoamyl alcohol for two hours and then cooled in an ice-bath.The resulting white product was collected by filtration andrecrystallized from methanol/ether to yield 4.53 g. (79%) of pure finalproduct, M.P. 251° C. The water solubility was found to be 20 mg./ml.

Analysis, Percent Calcd. for C₁₉ H₂₁ N₅ O₄.HCl: C, 54.35; H, 5.28; N,16.68. Found: C, 54.14; H, 5.21; N, 16.42.

EXAMPLE 5 A. 6-Chloro-7,8-dimethoxyquinazoline-2,4-dione (Xb)

Acetic acid (10.5 g., 0.175 mole) was added to a vigorously stirredsuspension of 5-chloro-3,4-dimethoxyanthranilic acid (28.9 g., 0.125mole) in 600 ml. water. Then 506 ml. 5% potassium cyanate (0.312 mole)solution was gradually added and stirred 1 hour at 40° C. After coolingthe reaction mixture to 20° C., 175 g. (4.37 moles) of sodium hydroxidepellets were added while maintaining the temperature below 40° C. Thereaction mixture was heated to 90° C. for 45 minutes. Upon cooling in anice bath, the sodium salt of the product precipitated, was filtered,resuspended in 125 ml. water, acidified with concentrated hydrochloricacid, cooled and filtered to yield 25.8 g. (80%) of colorless, pureproduct, M.P. 272°-3° C.

Analysis, Percent Calcd. for C₁₀ H₉ ClN₂ O₄ : C, 46.79; H, 3.53; N,10.92. Found: C, 46.87; H, 3.60; N, 10.90.

B. 6-Chloro-7-methoxyquinazoline-2,4-dione (XVIII)

Similarly, 6-chloro-7-methoxyquinazoline-2,4-dione was prepared from5-chloro-4-methoxyanthranilic acid in 83% yield, M.P. 356°-8° C.

Analysis, Percent Calcd. for C₉ H₇ ClN₂ O₃ : C, 47.70; H, 3.11; N,12.36. Found: C, 47.72; H, 3.44; N, 12.27.

EXAMPLE 6 A. 2,4,6-Trichloro-7,8-dimethoxyquinazoline (XIb)

A mixture of 6-chloro-7,8-dimethoxyquinazoline-2,4-dione (25.5 g., 0.099mole), phosphorous pentachloride (41.4 g., 0.199 mole) and 300 ml.phosphorous oxychloride was refluxed under nitrogen for three hours.Phosphorous oxychloride was removed in vacuo and residual POCl₃ wasazeotroped with toluene. The reddish-orange solid was dissolved in 200ml. dichloromethane and the solution was slowly added to ice-cold water.After stirring for 10 minutes the organic layer was separated, washedwith water, and dried over sodium sulfate. The filtrate was concentratedand 150 ml. hexane was added slowly to precipitate the product as a paleyellow solid which was recrystallized from toluene/ether to afford 18.0g. (62% yield), M.P., 154°-5° C.

Analysis, Percent Calcd. for C₁₀ H₇ Cl₃ N₂ O₂ : C, 40.91; H, 2.40; N,9.55. Found: C, 41.05; H, 2.48; N, 9.61.

B. 2,4,6-Trichloro-7-methoxyquinazoline (XIX)

Refluxing 6-chloro-7-methoxyquinazoline-2,4-dione with PCl₅ in POCl₃ asdescribed above afforded 2,4,6-trichloro-7-methoxyquinazoline in 74%yield, M.P., 150°-2° C.

Analysis, Percent Cald. for C₉ H₅ Cl₃ N₂ O: C, 41.02; H, 1.91; N, 10.63.Found: C, 40.90; H, 2.01; N, 10.54.

EXAMPLE 7 A. 2,6-Dichloro-4-amino-7,8-dimethoxyquinazoline (XIIb)

Ammonia was passed into a solution of2,4,6-trichloro-7,8-dimethoxyquinazoline (31.4 g., 0.107 mole) in 650ml. dry tetrahydrofuran for one hour at room temperature. After stirringfor an additional hour, the suspension was concentrated in vacuo andfiltered. The solid was resuspended in water, filtered, washed withwater and methanol. Recrystallization from dimethylformamide/wateryielded 23.7 g. (81%) of the desired product, M.P., 360° C.

Analysis, Percent Calcd. for C₁₀ H₉ Cl₂ N₃ O₂ : C, 43.82; H, 3.31; N,15.33. Found: C, 43.95; H, 3.53; N, 15.35.

B. 2,6-Dichloro-4-amino-7-methoxyquinazoline (XX)

Reaction of 2,4,6-trichloro-7-methoxyquinazoline with ammonia asdescribed above afforded 2,6-dichloro-4-amino-7-methoxyquinazoline as awhite solid, M.P., 300° C. in 58% yield.

Analysis, Percent Calcd. for C₉ H₇ Cl₂ N₃ O: C, 44.28; H, 2.89; N,17.22. Found: C, 44.12; H, 3.16; N, 17.19.

EXAMPLE 8 A.2-[4-(2-Furoyl)piperazine-1-yl]-4-amino-6-chloro-7,8-dimethoxyquinazolinehydrochloride(XIIIb)

A mixture of 2,6-dichloro-4-amino-7,8-dimethoxyquinazoline (1.50 g.,5.47 mmole) and 1-(2-furoyl)piperazine (1.08 g., 5.99 mmole) wasrefluxed in 40 ml. isoamyl alcohol for 2 hours and then cooledovernight. The resulting solid was filtered and recrystallized frommethanol/ether to yield 1.83 g. (74%) of pure final product, M.P.,208°-9° C.

Analysis, Percent Calcd. for C₁₉ H₂₀ ClN₅ O₄.HCl 1/2.H₂ O: C, 49.25; H,4.79; N, 15.17. Found: C, 49.03; H, 4.61; N, 15.35.

Water Solubility: 8 mg./ml.

B. 2-[4-(2-Furoyl)piperazine-1-yl]-4-amino-6-chloro-7-methoxyquinazolinehydrochloride

The title compound was prepared similarly by refluxing2,6-dichloro-4-amino-7-methoxyquinazoline and 1-(2-furoyl)piperazine inisoamyl alcohol, M.P. 229°-31° C., 79% yield.

Analysis, Percent Calcd. for C₁₈ H₁₈ ClN₅ O₃.HCl.H₂ O: C, 48.88; H,4.79; N, 15.83. Found: C, 49.47; H, 4.70; N, 15.62.

Water Solubility: 5 mg./ml.

EXAMPLE 9 A. 2-Methyl-2-hydroxypropyl4-[4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl]piperazine-1-carboxylatehydrochloride

A mixture of 2,6-dichloro-4-amino-7,8-dimethoxyquinazoline (1.50 g.,5.47 mmole) and 2-methyl-2-hydroxypropyl-4-piperazine-1-carboxylate(1.22 g., 6.03 mmole) was refluxed in 30 ml. methylisobutylketone fortwo days. The yellowish solid was filtered, resuspended in 40 ml.acetone and stirred for 15 minutes. The filtered solid was decolorizedwith charcoal and recrystallized twice from ethanol/ether to yield 1.47g. (57%) of final product, M.P., 211°-3° C.

Analysis Percent Calcd. for C₁₉ H₂₆ ClN₅ O₅.HCl; C, 47.90%; H, 5.50%; N,14.70%. Found: C, 47.70%; H, 5.74%; N, 14.36%.

Water Solubility: 35 mg./ml.

B. 2-ethyl-2-hydroxypropyl4-[4-amino-6-chloro-7-methoxyquinazolin-2-yl]piperazine-1-carboxylatehydrochloride [XXI, R¹ +R² =--COOCH₂ C(OH) (CH₃)₂ ]

The title compound was prepared similarly by refluxing2,6-dichloro-4-amino-7-methoxy quinazoline and2-methyl-2-hydroxypropyl-4-piperazine-1-carboxylate in methyl isobutylketone for 4 days, M.P. 243°-5° C., 69% yield.

Analysis Percent Calcd. for C₁₈ H₂₄ ClN₅ O₄.HCl.H₂ O C, 46.55%; H,5.86%; N, 14.08%.

Found: C, 46.89%; H, 5.67%; N, 15.22%.

Water Solubility: 6 mg./ml.

C.2-[4-(1,4-Benzodioxan-2-carbonyl)piperazin-1-yl]-4-amino-6-chloro-7-methoxyquinazolinehydrochloride

The title compound was prepared by the procedure of Part A, above, byrefluxing 2,6-dichloro-4-amino-7-methoxyquinazoline andN-(1,4-benzodioxan-2-carbonyl)piperazine in methylisobutylketone, M.P.194°-196° C.

EXAMPLE 10

When the appropriate N-substituted piperazine is employed in theprocedure of Example 4 in place of 1-(2-furoyl)piperazine, the analogousproducts tabulated below are obtained as the hydrochloride salts exceptas otherwise noted.

    __________________________________________________________________________    Example 10 (continued)                                                         ##STR43##                                                                                                   Elemental Analysis                                             Solubility                                                                         Empirical Calcd.:                                        W          M.P. °C.                                                                    mg./ml.                                                                            Formula   Found:                                                                            % C                                                                              % H                                                                              % N                                  __________________________________________________________________________    COOR.sup.5 ;                                                                  COOCH.sub.3                                                                              244-5                                                                              40   C.sub.16 H.sub.21 N.sub.5 O.sub.4.HCl                                                       50.56                                                                            5.78                                                                             18.25                                                                   49.69                                                                            5.74                                                                             18.24                                COOCH.sub.2 CH.sub.3                                                                     238-40                                                                             50   C.sub.17 H.sub.23 N.sub.5 O.sub.4.HCl                                                       50.74                                                                            6.13                                                                             17.41                                                     .0.25 H.sub.2 O                                                                             50.83                                                                            6.03                                                                             17.25                                COO(CH.sub.2).sub.2 CH.sub.3                                                             229-30                                                                             140  C.sub.18 H.sub.25 N.sub.5 O.sub.4.HCl                                                       52.48                                                                            6.36                                                                             17.00                                                                   52.28                                                                            6.37                                                                             16.82                                COO(CH.sub. 2).sub.3 CH.sub.3                                                            224-6                                                                              90   C.sub.19 H.sub.27 N.sub.5 O.sub.4.HCl                                                       53.58                                                                            6.63                                                                             16.44                                                                   53.28                                                                            6.34                                                                             16.22                                COO(CH.sub.2).sub.4 CH.sub.3                                                             114-6                                                                              40   C.sub.20 H.sub.29 N.sub.5 O.sub.4.HCl                                                       54.60                                                                            6.87                                                                             15.92                                                                   54.73                                                                            6.98                                                                             15.92                                COOCH.sub.2 CH(CH.sub.3).sub.2                                                           212-3.5                                                                            40   C.sub.19 H.sub.27 N.sub.5 O.sub.4.HCl                                                       53.58                                                                            6.63                                                                             16.44                                                                   53.82                                                                            6.70                                                                             15.79                                COOR.sup.5 :                                                                  COO(CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                   192  25   C.sub.20 H.sub.29 N.sub.5 O.sub.4.HCl                                                       54.60                                                                            6.87                                                                             15.92                                                                   54.99                                                                            7.18                                                                             15.91                                COOCH.sub.2 C(CH.sub.3).sub.2                                                            165-70                                                                             --   C.sub.19 H.sub.27 N.sub.5 O.sub.4.HCl                                                       48.66                                                                            6.66                                                                             14.93                                OH                   .0.5 H.sub.2 O                                                                              48.81                                                                            6.59                                                                             14.83                                COR.sup.4 :                                                                    ##STR44## 237-8                                                                              150  C.sub.19 H.sub.25 N.sub.5 O.sub.4.HCl .0.5 H.sub.2                                          52.71 53.03                                                                      6.29 5.95                                                                        16.18 16.16                           ##STR45## 237-8.5                                                                            11     --          -- -- --                                    ##STR46##   -- --     --          -- -- --                                    ##STR47## 251-3                                                                              --   C.sub.15 H.sub.19 N.sub.5 O.sub.3.HCl .H.sub.2                                              48.45 48.30                                                                      5.96 5.65                                                                        18.83 18.72                           ##STR48## 192-201                                                                            50   C.sub.21 H.sub.23 N.sub.5 O.sub.3.HCl .0.5 H.sub.2                                          57.46 56.99                                                                      5.74 5.66                                                                        15.96 15.87                           ##STR49##   -- --   C.sub.19 H.sub.26 N.sub.6 O.sub.3                                                           -- -- --                                    ##STR50## 150 (dec)                                                                          15   C.sub.23 H.sub.25 N.sub.5 O.sub. 5.HCl .H.sub.2                                             54.59 54.27                                                                      5.58 5.39                                                                        13.84 13.85                           ##STR51##   -- --     --          -- -- --                                    ##STR52## 158-61                                                                             --   C.sub.20 H.sub.27 N.sub.5 O.sub.3 (free                                                     62.32 62.10                                                                      7.06 7.27                                                                        18.17 18.19                          R.sup.3 :                                                                     CH.sub.2 CH.sub.2 OH                                                                     205-8                                                                              95   C.sub.16 H.sub.23 N.sub.5 O.sub.3.HCl                                                       48.71                                                                            6.54                                                                             18.94                                                                   50.01                                                                            6.55                                                                             18.85                                CH.sub.2 C.sub.6 H.sub.5                                                                 194-8                                                                              100  C.sub.21 H.sub.25 N.sub.5 O.sub.2.HCl                                                       55.80                                                                            6.69                                                                             15.49                                           (dec)     .2 H.sub.2 O  55.38                                                                            6.49                                                                             15.33                                C.sub.6 H.sub.5                                                                          185-7                                                                              25   C.sub.20 H.sub.23 N.sub.5 O.sub.2.HCl                                                       59.77                                                                            6.02                                                                             17.43                                                                   59.10                                                                            6.09                                                                             17.23                                3-CF.sub.3 C.sub.6 H.sub.4                                                               218-9                                                                               8   C.sub.21 H.sub.22 N.sub.5 O.sub.2 F.sub.3.HCl                                               53.67                                                                            4.93                                                                             14.90                                                                   53.97                                                                            4.88                                                                             15.12                                CH.sub.2 CHCH.sub.2                                                                      195-6                                                                              50   C.sub.17 H.sub.23 N.sub.5 O.sub.2.HCl                                                       54.46                                                                            6.72                                                                             18.68                                                     .0.5 H.sub.2 O                                                                              53.73                                                                            6.46                                                                             18.44                                __________________________________________________________________________

EXAMPLE 112-[4-(2-Furoyl-homopiperazine-1-yl]-4-amino-7,8-dimethoxyquinazolinehydrochloride

A. N-(2-Furoyl)homopiperazine

Homopiperazine (70 g., 0.70 mole) in 160 ml. water was treated with 6 Nhydrochloric acid to adjust to pH 5.5 Furoyl chloride (79.5 g., 0.60mole) and 25% (w/w) aqueous sodium hydroxide solution were addedsimultaneously to maintain a pH of 4.5-5.5. Then additional sodiumhydroxide was added to bring the mixture to pH 9.5. The solution wasextracted with chloroform, dried over anhydrous potassium carbonate anddistilled to afford 63 g. of product, B.P. 124°-130° C. at 10 mm.

B. 4-Amino-2-chloro-7,8-dimethoxyquinazoline (1.76 g., 7.3 mole),N-(2-furoyl)homopiperazine (1.50 g., 7.7 mole) and 40 ml. of isoamylalcohol were combined and the mixture heated at reflux under a nitrogenatmosphere for 1.5 hours. After cooling to room temperature, the mixturewas stirred for one hour, filtered and the precipitated product washedwith ether and recrystallized from methanol/ether to afford 2.15 g. ofthe title compound, M.P. 182°-183° C.

Analysis, Percent Calcd. for C₂₀ H₂₃ N₅ O₄.HCl.0.5 H₂ O: C, 54.23; H,5.69; N, 15.81. Found: C, 53.84; H, 5.40; N, 15.49.

The solubility in water was found to be 30 mg./ml.

EXAMPLE 122-[4-(2-Tetrahydrofuroyl)homopiperazin-1-yl]-4-amino-7,8-dimethoxyquinazolinehydrochloride

A. N-(2-Tetrahydrofuroyl)homopiperazine

N-(2-Furoyl)homopiperazine (33.0 g.) in 200 ml. of ethanol washydrogenated over 5% rhodium-on-carbon catalyst at three atmospherespressure. The catalyst was removed by filtration and the productdistilled to give the desired product, B.P. 135° at 1 mm.

B. 4-Amino-2-chloro-7,8-dimethoxyquinazoline (2.10 g., 8.75 mmole),N-(2-tetrahydrofuroyl)homopiperazine [1.9 g., 9.58 mmole) and 50 ml. ofisoamyl alcohol were mixed and heated at reflux under nitrogen for 2.5hours. The solvent was removed by evaporation in vacuo, the residuedissolved in water and filtered through a mixture of activated carbonand diatomaceous earth. The filtrate was adjusted to an alkaline pH byaddition of sodium bicarbonate solution, extracted four times with 50ml. portions of ethyl acetate and the extracts dried over sodiumsulfate. The solvent was evaporated and the residue chromatographed on30 g. of silica gel, eluting with chloroform/ethanol. The fractionscontaining the desired product (free base) were combined and evaporatedto afford the free base as a foam, 1.0 g. The free base was dissolved inether, saturated hydrogen chloride and filtered to obtain the titlecompound, M.P. 130° (dec.).

Analysis, Percent Calcd. for C₂₀ H₂₇ N₅ O₄.HCl.0.50 H₂ O: C, 53.74; H,6.54; N, 15.67. Found: C, 53.56; H, 6.68; N, 15.44.

Water Solubility: 120 mg./ml.

EXAMPLE 13 A.2-(4-Benzylpiperidin-1-yl)-4-amino-7,8-dimethoxyquinazolinehydrochloride

4-Amino-2-chloro-7,8-dimethoxyquinazoline (2.40 g., 10 mmole),4-benzylpiperidine (1.93 g., 11 mmole) and 50 ml. of isoamyl alcoholwere heated at reflux under a nitrogen atmosphere for two hours andcooled to room temperature. Diethyl ether (50 ml.) was added and themixture allowed to stand in the refrigerator for two days. Theprecipitated solid was collected by filtration and recrystallized fromethanol/diethyl ether to afford 2.50 g. (60%) of the title compound,M.P. 216°-217° C.

Analysis, Percent Calcd. for C₂₂ H₂₆ O₂ N₄.HCl C, 63.68; H, 6.56; N,13.50. Found: C, 63.78; H, 6.67; N, 13.89.

Water Solubility: 6 mg./ml.

EXAMPLE 14

Employing the appropriately substituted 2-chloro-(or 2-bromo) 4-aminoquinazoline and amine of formula ##STR53## in the procedure of Example13 the following products are obtained ##STR54## where a is 1 or m and mand n are 2, or 3.

    ______________________________________                                        Y.sup.1                                                                           Y.sup.2   Y.sup.3   a   n   R.sup.7                                       ______________________________________                                        H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   CH.sub.3                                      Cl  CH.sub.3 O                                                                              H         1   2   CH.sub.3 (CH.sub.2).sub.5                     Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   (CH.sub.3).sub.2 CHCH.sub.2                   H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       1   2   C.sub.6 H.sub.5                               Cl  C.sub.2 H.sub.5 O                                                                       H         1   2   C.sub.6 H.sub.5 CH.sub.2                      Cl  C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       1   2   3-CH.sub.3 C.sub.6 H.sub.4                    H   nC.sub.3 H.sub.7 O                                                                      CH.sub.3 O                                                                              1   3   (CH.sub.3).sub.2 CH                           Cl  nC.sub.3 H.sub.7 O                                                                      H         1   3   CH.sub.3 (CH.sub.2).sub.4                     Cl  nC.sub.3 H.sub.7 O                                                                      n-C.sub.3 H.sub.7 O                                                                     1   3   3-FC.sub.6 H.sub.4                            H   CH.sub.3 O                                                                              H         1   3   4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2          Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   4-HOC.sub.6 H.sub.4                           Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   3-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4           H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   2-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4                                         CH.sub.2                                      Cl  CH.sub.3 O                                                                              H         2   3   CH.sub.3 CH.sub.2                             Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   3   4-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4         H   C.sub.2 H.sub.5 O                                                                       H         2   3   CH.sub.3 (CH.sub.2).sub.3                     Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   3   4-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2           Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   3   4-FC.sub.6 H.sub.4                            H   CH.sub.3 O                                                                              n-C.sub.3 H.sub.7 O                                                                     3   3   CH.sub.3                                      Cl  n-C.sub.3 H.sub.7 O                                                                     H         3   3   C.sub.6 H.sub.5                               Cl  CH.sub.3 O                                                                              H         3   3   C.sub.6 H.sub.5 CH.sub.2                      H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              3   3   4-CH.sub.3 C.sub.6 H.sub.4                    Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   3   2-ClC.sub.6 H.sub.4 CO                        Cl  CH.sub.3 O                                                                              H         1   3   C.sub.6 H.sub.5 CO                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   4-BrC.sub.6 H.sub.4 CO                        Cl  CH.sub.3 O                                                                              H         1   2   4-HOC.sub.6 H.sub.4 CO                        Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   4-CF.sub.3 C.sub.6 H.sub.4 CO                 H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   3   4-FC.sub.6 H.sub.4 CO                         Cl  CH.sub.3 O                                                                              H         3   3   3-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4 CO        Cl  CH.sub.3 O                                                                              H         1   3   C.sub.6 H.sub.5 CO                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   HOCH.sub.2                                    Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   HOCH.sub.2 CH.sub.2                           Cl  CH.sub.3 O                                                                              H         1   2   (CH.sub.3).sub.2 C(OH)CH.sub.2                H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   3   (CH.sub.3).sub.2 CHCH(OH)CH.sub.2             Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   3   (CH.sub.3).sub.2 C(OH)CH.sub.2 CH.sub.2       Cl  CH.sub.3 O                                                                              H         1   3   (CH.sub.3).sub.2 C(OH)                        H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   CH.sub.2 OH                                   Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   CH.sub.2 CH.sub.2 OH                          Cl  CH.sub.3 O                                                                              H         2   2   CH.sub.3 CH(OH)                               H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       3   3   CH.sub.2 OH                                   Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              3   3   (CH.sub.3).sub.2 C(OH)                        Cl  CH.sub.3  H         3   3   (CH.sub.3 CH.sub.2).sub.2 C(OH)               ______________________________________                                    

EXAMPLE 152-[4-(2-Tetrahydrofuroyl)piperazin-1-yl]-4-amino-6-chloro-7,8-dimethoxyquinazoline

To 35 ml. of isoamyl alcohol were added 1.50 g. (5.47 mmole) of4-amino-2,6-dichloro-7,8-dimethoxyquinazoline and 1.11 g. (6.02 mmole)of 1-(2-tetrahydrofuroyl)piperazine and the mixture was heated at refluxunder a nitrogen atmosphere for 1.5 hours. The mixture was cooled, 20ml. of ethyl ether was added and the resulting mixture stirred at roomtemperature overnight. It was then cooled in ice and the precipitatedsolid collected by filtration. The crude material was recrystallizedonce from a mixture of isopropanol, methanol and ethyl ether. Therecrystallized material was dissolved in water made strongly alkalinewith sodium hydroxide solution while stirring, the precipitated brownishsolid collected by filtration, dried, decolorized with activated carbonand recrystallized from isopropanol/ethyl ether to obtain 0.38 g. ofyellow solid, M.P. 192°-193° C.

Analysis, Percent Calcd. for C₁₉ H₂₄ O₄ N₅ Cl: C, 54.09; H, 5.73; N,16.60. Found: C, 53.83; H, 5.73; N, 16.58.

Mass spectrum peaks (M⁺ /e); 421 (molecular ion), 406, 392, 378, 350,321, 293, 280 and 266.

EXAMPLE 16

Employing the procedures of Examples 8, 9 and 10 the following compoundsare similarly prepared from the appropriate starting materials.

    ______________________________________                                         ##STR55##                                                                    Y.sup.1                                                                           Y.sup.2   Y.sup.3   W                                                     ______________________________________                                        H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              H                                                     Cl  C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       CH.sub.3                                              H   n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     CH.sub.2 CH(CH.sub.3).sub.2                           Cl  iso-C.sub.3 H.sub.7 O                                                                   H         CH.sub.2 (CH.sub.2).sub.4 CH.sub.3                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2 CHCH.sub.2                                   Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2 C(CH.sub.3)CH.sub.2                          H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       CH.sub.2 CHCHCH.sub.3                                 Cl  C.sub.2 H.sub.5 O                                                                       H         CH.sub.2 C(CH.sub.3)CHCH.sub.3                        H   n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     CH.sub.2 (CH.sub.2).sub.2 CHCH.sub.2                  Cl  n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     CH.sub.2 CH.sub.2 OH                                  H   iso-C.sub.3 H.sub.7 O                                                                   CH.sub.3 O                                                                              CH.sub.2 CH.sub.2 OH                                  Cl  CH.sub.3 O                                                                              H         CH.sub.2 CH(OH)CH.sub.3                               H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2 C(OH)(CH.sub.3).sub.2                        Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH(CH.sub.3)CH(CH.sub.3)CH.sub.2 OH                   H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       CH.sub.2 C(CH.sub.3).sub.2 CH.sub.2 OH                Cl  C.sub.2 H.sub.5 O                                                                       H         C(CH.sub.3).sub.2 C(OH)CH.sub.3                       H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       cyclopropyl                                           Cl  n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     cyclopentyl                                           H   n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     cyclohexyl                                            Cl  CH.sub.3 O                                                                              H         cyclooctyl                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-ClC.sub.6 H.sub.4                                   Cl  CH.sub.3 O                                                                              H         2-FC.sub.6 H.sub.4                                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                  Cl  CH.sub.3 O                                                                              H         3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-HOC.sub.6 H.sub.4                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4                   Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4                 Cl  C.sub.2 H.sub.5 O                                                                       H         4-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4 CH.sub.2        Cl  C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       4-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4 CH.sub.2          Cl  C.sub.2 H.sub.5 O                                                                       H         4-BrC.sub.6 H.sub.4 CH.sub.2                          Cl  C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       2-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2                   Cl  C.sub.2 H.sub.5 O                                                                       H         3-FC.sub.6 H.sub.4 CH.sub.2                           Cl  CH.sub.3 O                                                                              H         2-fluoro-1-naphthyl                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-bromo-2-naphthyl                                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-methyl-1-naphthyl                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              3-trifluoromethyl-1-naphthyl                          Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2-hydroxy-1-naphthyl                                  H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-hydroxy-1-naphthylmethyl                            Cl  CH.sub.3 O                                                                              H         4-methoxy-2-naphthylmethyl                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              3-fluoro-1-napthylmethyl                              H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              6-methylsulfonylamino-1-                                                      napthylmethyl                                         H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-methylsulfonyl-1-naphthyl                           H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2 C CH                                         Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2 C CCH.sub.3                                  Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2 C CCH.sub.2 CH.sub.3                         H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2 (CH.sub.2).sub.2 C CH                        Cl  CH.sub.3 O                                                                              H         CHO                                                   Cl  CH.sub.3 O                                                                              H         COCH.sub.3                                            H   iso-C.sub.3 H.sub.7 O                                                                   iso-C.sub.3 H.sub.7 O                                                                   COCH(CH.sub.3).sub.2                                  H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       COCH.sub.2 (CH.sub.2).sub.4 CH.sub.3                  Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              COCH.sub.2 (CH.sub.2).sub.2 CH(CH.sub.3).sub.2        Cl  CH.sub.3 O                                                                              H         COCH.sub.2 CHCH.sub.2                                 H   n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     COCH.sub.2 C(CH.sub.3)CH.sub.2                        Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              COCH.sub.2 C(CH.sub.3)CHCH.sub.3                      Cl  CH.sub.3 O                                                                              H         COCH.sub.2 C  CH                                      H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              COCH.sub.2 C CCH.sub.3                                H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              COC CCH.sub.2 CH.sub.2 CH.sub.3                       Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              cyclopropylcarbonyl                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              cyclobutylcarbonyl                                    H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       cycloheptylcarbonyl                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              cyclooctylcarbonyl                                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              cyclopropylmethylcarbonyl                             Cl  CH.sub.3 O                                                                              H         cyclooctylmethylcarbonyl                              Cl  CH.sub.3 O                                                                              H         3-thenoyl                                             H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              5-chloro-2-thenoyl                                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-methyl-3-thenoyl                                    Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              5-phenyl-2-thenoyl                                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              5-ethyl-3-furoyl                                      H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              5-phenyl-2-furoyl                                     H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2-pyridylcarbonyl                                     H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2-chloro-4-pyridylcarbonyl                            Cl  CH.sub.3 O                                                                              H         2-methyl-4-pyrimidinylcarbonyl                        H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2-phenyl-4-pyrimidinylcarbonyl                        H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR56##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR57##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR58##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR59##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR60##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR61##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR62##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR63##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR64##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR65##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR66##                                            Cl  CH.sub.3 O                                                                              H         1-hydroxy-2-naphthoyl                                 H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-chloro-1-naphthylmethyl-                                                    carbonyl                                              Cl  CH.sub.3 O                                                                              H                                                                                        ##STR67##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR68##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR69##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR70##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR71##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR72##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR73##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR74##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR75##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR76##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR77##                                            Cl  CH.sub.3 O                                                                              H         CH.sub.3 OCO                                          H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.3 (CH.sub.2).sub.5 CH.sub.2 OCO                Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              cyclohexyl OCO                                        H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              HOCH.sub.2 CH.sub.2 OCO                               Cl  CH.sub.3 O                                                                              H         (CH.sub.3).sub.2 C(OH)CH.sub.2 CH.sub.2 OCO           Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-BrC.sub.6 H.sub.4 CH.sub.2 OCO                      H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1-hydroxy-2-naphthylmethyl-OCO                        H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2CHCH.sub.2 OCO                                Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              CH.sub.2C(CH.sub.3)CH.sub.2 OCO                       Cl  CH.sub.3 O                                                                              H         CH.sub.3 CHC(CH.sub.3)CH.sub.2 OCO                    Cl  C.sub.2 H.sub.5 O                                                                       H         cyclopropyl-OCO                                       Cl  n-C.sub.3 H.sub.7 O                                                                     H         cyclohexyl-OCO                                        H   n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     cycloheptyl-OCO                                       Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              cyclooctyl-OCO                                        Cl  C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       CH.sub.3 CH(OH)CH.sub.2 OCO                           H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       2-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2 OCO               Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              3-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2 OCO               Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2 OCO              Cl  CH.sub.3 O                                                                              H         4-HOC.sub.6 H.sub.4 CH.sub.2 OCO                      Cl  CH.sub. 3 O                                                                             H         3-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4 CH.sub.2 OCO      H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4 CH.sub.2                                OCO                                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              4-chloro-1-naphthylmethyl-OCO                         Cl  CH.sub.3 O                                                                              H         1-fluoro-2-naphthylmethyl-OCO                         Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              3-hydroxy-2-naphthylmethyl-OCO                        Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2-methyl-1-naphthylmethyl-OCO                         H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1-methoxy-2-naphthylmethyl-OCO                        Cl  CH.sub.3 O                                                                              H         4-trifluoromethyl-1-naphthyl-                                                 methyl-OCO                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR78##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR79##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR80##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR81##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR82##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR83##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR84##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR85##                                            H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                        ##STR86##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR87##                                            Cl  C.sub.2 H.sub.5 O                                                                       H                                                                                        ##STR88##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR89##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR90##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR91##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR92##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR93##                                            Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR94##                                            Cl  CH.sub.3 O                                                                              H                                                                                        ##STR95##                                            H   CH.sub.3 O                                                                              CH.sub.3 O                                                                               ##STR96##                                            ______________________________________                                    

EXAMPLE 17 A. 3-Chloro-4-methoxy-6-isothiocyanatobenzonitrile

To a solution of 27.4 g. (0.15 mole) of6-amino-3-chloro-4-methoxybenzonitrile in 150 ml. of 1,2-dichloro-ethaneat 0°-5° C. is added with stirring a mixture of 23 g. (0.2 mole)thiophosgene, 100 ml. 1,2-dichloroethane, 20 g. (0.2 mole) calciumcarbonate and 200 ml. of water. After the addition the mixture isstirred for one hour at 0°-5° C., warmed to 20° C. and stirred for 6hours at this temperature and finally at 35° C. for an hour. Thereaction mixture is filtered and the organic layer separated, washedwith dilute hydrochloric acid, water and dried (MgSO₄). The solvent isremoved by evaporation and the residue used without purification in thenext step.

B. 3-Chloro-4-methoxy-6-(homomorpholin-4-yl)thiocarbamidobenzonitrile

To 11.3 g. (0.05 mole) of the above residue dissolved in 65 ml. of ethylacetate is slowly added with stirring at 0° C., a solution of 5.1 g.(0.05 mole) of homomorpholine in an equal volume of the same solvent.The resulting mixture is cooled to -25° C. and allowed to standovernight. The precipitate is collected by filtration, washed with coldethyl acetate and dried to obtain the desired product.

C.N-(3-Methoxy-4-chloro-6-cyanophenyl)-(homomorpholin-4-yl)-methylthioformamidate

In 200 ml. of diglyme (diethylene glycol dimethylether) is dissolved16.3 g. (0.05 mole) of3-chloro-4-methoxy-6-(homomorpholin-4-yl)-thiocarbamidobenzonitrile and14.2 g. (0.1 mole) of methyl iodide and the mixture heated at reflux(60° C.) for eight hours then cooled to room temperature. The resultingmixture is filtered, the solid product washed with ether and dried toobtain the hydroiodide salt of the title compound.

The hydroiodide salt is dissolved in 150 ml. of methanol and 90 ml. of25% ammonium hydroxide is added with stirring. The resulting mixture isstirred for two hours at 0° C., filtered and washed with ether to obtainthe title compound as the free base.

D. 2-(Homomorpholin-4-yl)-4-amino-6-chloro-7-methoxyquinazoline

To a solution of 3.4 g. (0.01 mole) of the free base obtained in Part C,above, in 75 ml. of formamide is added 1.3 g. of sodium amide and theresulting solution is cooled to 0° C. and saturated with ammonia gas.The cold solution is warmed slowly over 2-3 hours to 120° C., thenmaintained at this temperature for 4 hours. The reaction mixture is thencooled to room temperature, 100 ml. of ice-water added, the mixtureextracted with chloroform, the extracts washed with water, dried andevaporated to dryness. The crude residual product is purified bycrystallization.

EXAMPLE 18

Employing one of the procedures of Examples 4, 8, 9 and 17, thefollowing compounds are prepared from the appropriate startingmaterials.

    ______________________________________                                         ##STR97##                                                                    Y.sup.1                                                                           Y.sup.2 Y.sup.3  R.sup.1     R.sup.2                                      ______________________________________                                        H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           H                                            H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           CH.sub.3                                     Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           (CH.sub.3).sub.2 CH                          Cl  CH.sub.3 O                                                                            H        H           (CH.sub.3).sub.2 CHCH(CH.sub.3)              Cl  C.sub.2 H.sub.5 O                                                                     H        CH.sub.3    CH.sub.3                                     H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             CH.sub.3 (CH.sub.2).sub.3 CH.sub.2                                                        CH.sub.3 CH.sub.2                            Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             CH.sub.3 (CH.sub.2).sub.3 CH.sub.2                                                        CH.sub.3 (CH.sub.2).sub.3 CH.sub.2           Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           cyclopropyl                                  Cl  CH.sub.3 O                                                                            H        CH.sub.3    cyclopentyl                                  H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           cyclooctyl                                   H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             cyclopropyl cyclopropyl                                  Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             cyclohexyl  cyclohexyl                                   Cl  CH.sub.3 O                                                                            H        cyclohexyl  cyclooctyl                                   Cl  CH.sub.3 O                                                                            H        CH.sub.2CHCH.sub.2                                                                        CH.sub.2CHCH.sub.2                           H n-C.sub.3 H.sub.7 O                                                                 n-C.sub.3 H.sub.7 O                                                                    CH.sub.2CH(CH.sub.2).sub.3                                                                  CH.sub.2CH(CH.sub.2).sub.3                     Cl  CH.sub.3 O                                                                            H        CH.sub.2C(CH.sub.3)CH.sub.2                                                               CH.sub.2C(CH.sub.3)CH.sub.2                  Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             CH.sub.3    CH.sub.2CHCH.sub.2                           Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           CH.sub.2CHCH.sub.2                           H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           (CH.sub.3).sub.2 CCHCH.sub.2                 H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           CHCCH.sub.2                                  Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           CHC(CH.sub.2).sub.3                          Cl  CH.sub.3 O                                                                            H        CH.sub.3 CH.sub.2 CH.sub.2                                                                CHCCH.sub.2                                  Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             cyclopropyl CH.sub.3 C CCH.sub.2                         Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             cyclohexyl  CHCCH.sub.2                                  H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             CH.sub.2CHCH.sub.2                                                                        CHCCH.sub.2                                  H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             CH.sub.3 (CH.sub.2).sub.4 CH.sub.2                                                        CH.sub.2CHCH.sub.2                           Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             cyclooctyl  CH.sub.3 CHCHCH.sub.2                        Cl  CH.sub.3 O                                                                            H        CH.sub.3 (CH.sub.2).sub.3 CH.sub.2                                                        (CH.sub.3).sub.2 CCHCH.sub.2                 Cl  CH.sub.3 O                                                                            H        HOCH.sub.2 CH.sub.2                                                                       HOCH.sub.2 CH.sub.2                          H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           HO(CH.sub.2).sub.5                           Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             H           HOCH.sub.2 CH.sub.2                          Cl  CH.sub.3 O                                                                            H        HO(CH.sub.2).sub.5                                                                        HO(CH.sub.2).sub.5                           Cl  CH.sub.3 O                                                                            H        CH.sub.3    HOCH.sub.2 CH.sub.2 CH.sub.2                 H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             (CH.sub.3).sub.2 CHCH.sub.2 CH.sub.2                                                      HOCH.sub.2 CH.sub.2                          Cl  CH.sub.3 O                                                                            CH.sub.3 O                                                                             cyclohexyl  CH.sub.3 CH(OH)CH.sub.2                      Cl  CH.sub.3 O                                                                            H        CH.sub.2CHCH.sub.2                                                                        (CH.sub.3).sub.2 C(OH)CH.sub.2               H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             CHCCH.sub.2 HO(CH.sub.2).sub.5                           H   CH.sub.3 O                                                                            CH.sub.3 O                                                                             cyclopropyl HOCH.sub.2 CH.sub.2                          ______________________________________                                    

EXAMPLE 19 A. 2-(3-Thiazolidinyl)-4-amino-7,8-dimethoxyquinazolineHydrochloride

A mixture of 4.8 g. (0.02 mole) of4-amino-2-chloro-7,8-dimethoxyquinazoline and 4.5 g. (0.05 mole) ofthiazolidine in 50 ml. of chlorobenzene is heated at reflux for 18hours, cooled to room temperature and the precipitate collected byfiltration to give the title compound which was purified byrecrystallization.

B. 2-(3-Thiazolidinyl)-4-amino-7,8-dimethoxyquinazoline S-oxide

The product obtained in Part A, 1.0 g., is converted to the free base bypartitioning between dilute aqueous sodium hydroxide and methylenechloride. The organic extracts are dried and concentrated in vacuo to100 ml. To the methylene chloride solution of free base at 0° C. isadded dropwise over 15 minutes a solution of 0.60 g. ofm-chloroperbenzoic acid in 25 ml. of the same solvent. After stirringfor 2 hours at 0° C. the reaction mixture is washed with dilute sodiumbicarbonate and water. The organic extracts are dried (NaSO₄) andevaporated to dryness in vacuo to obtain the title S-oxide whichpurified by recrystallization, if desired.

The title compound is also obtained by the procedure of Part A, above,when thiazolidine-S-oxide is employed as starting material in place ofthiazolidine.

C. 2-(3-Thiazolidinyl)-4-amino-7,8-dimethoxyquinazoline S,S-Dioxide

A mixture of 9.6 g. (0.04 mole) of4-amino-2-chloro-7,8-dimethoxyquinazoline and 10.0 g. of thiazolidineS,S-dioxide in 200 ml. of chlorobenzene is heated at reflux for 24hours, cooled to room temperature and the product collected byfiltration. The crude title compound is purified, if desired, byrecrystallization.

D.

Employing the above procedures or those of Examples 4, 8 or 17 thefollowing compounds are similarly obtained from the appropriate startingmaterials.

    ______________________________________                                         ##STR98##                                                                    Y.sup.1 Y.sup.2    Y.sup.3  NR.sup.1 R.sup.2                                  ______________________________________                                        H       CH.sub.3 O CH.sub.3 O                                                                              ##STR99##                                        Cl      CH.sub.3 O H                                                                                       ##STR100##                                       Cl      CH.sub.3 O CH.sub.3 O                                                                              ##STR101##                                       H       CH.sub.3 O CH.sub.3 O                                                                              ##STR102##                                       Cl      CH.sub.3 O H                                                                                       ##STR103##                                       Cl      CH.sub.3 O CH.sub.3 O                                                                              ##STR104##                                       H       C.sub.2 H.sub.5 O                                                                        C.sub.2 H.sub.5 O                                                                       ##STR105##                                       Cl      n-C.sub.3 H.sub.7 O                                                                      n-C.sub.3 H.sub.7 O                                                                     ##STR106##                                       Cl      CH.sub.3 O H                                                                                       ##STR107##                                       H       CH.sub.3 O CH.sub.3 O                                                                              ##STR108##                                       Cl      CH.sub.3   CH.sub.3 O                                                                              ##STR109##                                       Cl      CH.sub.3 O H                                                                                       ##STR110##                                       ______________________________________                                    

EXAMPLE 20 A.2-(3-Hydroxypyrrolidin-1-yl)-4-amino-6-chloro-7,8-dimethoxyquinazolinehydrochloride

A mixture of 4-amino-2,6-dichloro-7,8-dimethoxyquinazoline (5.48 g.,0.020 mole) and 3-pyrrolidinol (2.18 g., 0.025 mole) in 150 ml. ofisoamyl alcohol is heated at reflux for five hours then cooled in ice.The precipitated product is collected by filtration and purified byrecrystallization to obtain the title compound.

B.2-[4-(2-Ethoxyethoxy)piperidin-1-yl]-4-amino-6-chloro-7,8-dimethoxyquinoxazolinehydrochloride

4-Amino-2,6-dichloro-7,8-dimethoxyquinazoline (4.9 g.),4-(2-ethoxyethoxy)piperidine (3.2 g.) and triethylamine (10 ml.) inn-butanol (400 ml.) are heated at reflux overnight under an atmosphereof nitrogen. The mixture is then cooled, evaporated in vacuo, and theresidue basified (aqueous Na₂ CO₃) and extracted 3 times withchloroform. The combined chloroform extracts are evaporated and theresidue chromatographed on neutral alumina to give the crude productwhich is converted to the hydrochloride salt by treatment with hydrogenchloride in ethanol to afford the title compound.

C.

By the above procedures the following compounds are similarly providedfrom the appropriate starting materials in each case.

    __________________________________________________________________________     ##STR111##                                                                   Y.sup.1                                                                         Y.sup.2                                                                           Y.sup.3                                                                           NR.sup.1 R.sup.2                                                    __________________________________________________________________________    H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR112##                                                         Cl                                                                              CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR113##                                                         Cl                                                                              CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR114##                                                         H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR115##                                                         H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR116##                                                         H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR117##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR118##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR119##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR120##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR121##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR122##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR123##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR124##                                                         H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR125##                                                         H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR126##                                                         H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR127##                                                         Cl                                                                              CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR128##                                                         Cl                                                                              CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR129##                                                         Cl                                                                              CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR130##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR131##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR132##                                                         H CH.sub.3 O                                                                        CH.sub.3 O                                                                         ##STR133##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR134##                                                         Cl                                                                              CH.sub.3 O                                                                        H                                                                                  ##STR135##                                                         __________________________________________________________________________

EXAMPLE 21 A.2-(Octamethyleneimin-1-yl)-4-amino-7,8-dimethoxyquinazolinehydrochloride

To 500 ml. of isoamyl alcohol is added 23.9 g. (0.10 mole)4-amino-2-chloro-7,8-dimethoxyquinazoline and 14.0 g. (0.11 mole)octamethyleneimine and the mixture is heated at reflux for 3.5 hours.After cooling, the precipitated solid is collected, washed with etherand dried to obtain the title compound.

B. By employing the above procedure with the appropriate startingmaterials in each case the following compounds are similarly provided.

    ______________________________________                                         ##STR136##                                                                   Y.sup.1  Y.sup.2      Y.sup.3  2p + n                                         ______________________________________                                        H        CH.sub.3 O   CH.sub.3 O                                                                             4                                              Cl       CH.sub.3 O   CH.sub.3 O                                                                             5                                              H        C.sub.2 H.sub.5 O                                                                          C.sub.2 H.sub.5 O                                                                      6                                              Cl       C.sub.2 H.sub.5 O                                                                          C.sub.2 H.sub.5 O                                                                      7                                              H        n-C.sub.3 H.sub.7 O                                                                        n-C.sub.3 H.sub.7 O                                                                    8                                              Cl       iso-C.sub.3 H.sub.7 O                                                                      H        9                                              Cl       CH.sub.3 O   H        4                                              Cl       CH.sub.3 O   H        5                                              Cl       CH.sub.3 O   CH.sub.3 O                                                                             4                                              H        CH.sub.3 O   CH.sub.3 O                                                                             5                                              ______________________________________                                    

EXAMPLE 22 2-(3-Methylpiperidin-1-yl)-4-amino-7,8-dimethoxyquinazoline

Equimolar amounts (0.10 mole) of7,8-dimethoxy-2,4-(1H,3H)-quinazolinedione and phosphorous oxychlorideare stirred at room temperature overnight and the volatiles evaporatedin vacuo to afford a residue of2-chloro-7,8-dimethoxy-4-(3H)-quinazolineone which is purified bywashing with aqueous sodium bicarbonate, extraction with chloroform andevaporation of solvent. To the residue is added a solution of 0.10 moleof 3-methylpiperidine in 300 ml. of isoamyl alcohol and the mixtureheated at reflux for three hours, the solvent is then evaporated invacuo to afford2-(3-methylpiperidin-1-yl)-7,8-dimethoxy-4(3H)-quinazolineonehydrochloride. To this is added 150 ml. of phosphorous oxychloride andthe resulting mixture is heated at reflux for two hours. The liquids areevaporated to give a residue of2-(3-methylpiperidin-1-yl)-4-chloro-7,8-dimethoxyquinazolinehydrochloride. The product is dissolved in dilute aqueous sodiumbicarbonate, extracted with chloroform, dried (Na₂ SO₄) and the solventevaporated.

The above product is dissolved in 350 ml. of tetrahydrofuran and asolution of anhydrous ammonia (5.3 g.) in the same solvent is added. Themixture is stirred at room temperature for 24 hours, the precipitatecollected by filtration and purified by recrystallization to obtain thetitle compound.

EXAMPLE 232-(3-n-Hexylpyrrolidin-1-yl)-4-amino-6-chloro-7,8-dimethoxyquinazoline

To 12 grams of 6-chloro-7,8-dimethoxy-2,4-(1H,3H)-quinazolinedione in200 ml. of pyridine is added 30 g. of phosphorous pentasulfide and themixture is refluxed with continuous stirring for five hours. The solventis evaporated in vacuo and the residue decomposed with hot water. Thesolid material is filtered to obtain6-chloro-7,8-dimethoxy-2,4-(1H,3H)-quinazolinedithione.

To 0.1 mole of 6-chloro-7,8-dimethoxy-2,4-(1H,3H)-quinazolinedithione in220 ml. 1 N potassium hydroxide solution and 100 ml. methanol, is addedslowly with stirring, 0.22 mole of methyl iodide. The mixture is heatedon a steam bath for 2 hours, cooled, and the resulting precipitate isfiltered from the mixture. The product is6-chloro-2,4-dimethylmercapto-7,8-dimethoxyquinazoline.

To 0.1 mole of 6-chloro-2,4-dimethylmercapto-7,8-dimethoxyquinazoline in200 ml. of tetrahydrofuran is added a solution of 0.1 mole of anhydrousammonia in tetrahydrofuran. The mixture is stirred at room temperaturefor 18 hours and the precipitate which forms is collected andrecrystallized from dimethylformamide/water to yield2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline.

A mixture of 0.1 mole of2-methylmercapto-4-amino-6-chloro-7,8-dimethoxyquinazoline and 0.12 moleof 3-n-hexylpyrrolidine in isoamyl alcohol is heated at reflux for 16hours, cooled, washed with water and the organic phase is concentratedin vacuo. Hexane is slowly added to the residue and the solid titlecompound is collected and purified, if desired by silica gel columnchromatography.

EXAMPLE 242-[4-(2,3-Dihydro-4H-benzopyran-2-carbonyl)-piperazin-1-yl]-4-amino-6-chloro-7-methoxyquinazolinehydrochloride

To 0.10 mole of 2-(piperazin-1-yl)-4-amino-6-chloro-7-methoxyquinazolinein 300 ml. of methanol is added with vigorous stirring, 0.10 mole of2,3-dihydro-4H-benzopyran-2-carboxylic acid chloride. After the additionis complete, the mixture is stirred for three hours at room temperatureand the precipitated title compound is collected by filtration.

EXAMPLE 25 2-Diethylamino-4-amino-6-chloro-7-methoxyquinazoline

To 0.1 mole of 2,5-dichloro-4-methoxybenzonitrile in dimethylformamide(300 ml.) is added 0.5 mole of N,N-diethylguanidine and the mixture isheated at 150° C. for 12 hours. The solution is concentrated in vacuo toa small volume and poured into ice-water. The precipitated solid iscollected by filtration and the crude product purified by silica gelcolumn chromatography.

When 2-amino-5-chloro-4-methoxybenzontrile or2-amidino-5-chloro-4-methoxyaniline is employed in the above reaction inplace of 2,5-dichloro-4-methoxybenzonitrile the same compound isobtained.

EXAMPLE 262-(N-methyl-N-cyclohexylamino)-4-amino-6-chloro-7,8-dimethoxyquinazoline

A. To 5 liters of ethanol containing 0.2 mole of sodium ethoxide isadded slowly with stirring 0.1 mole each of phenol and2,4,6-trichloro-7,8-dimethoxyquinazoline. The mixture is heated toboiling then allowed to stand at room temperature overnight, poured intoice-water, stirred 15 minutes and the precipitate collected byfiltration. The cake is washed with water, then cold ethanol, dried andrecrystallized from ethanol/hexane to obtain2,6-dichloro-7,8-dimethoxy-4-ethoxyquinazoline.

B. A mixture of 0.1 mole of the above product and 0.11 mole ofN-methylcyclohexylamine in 350 ml. of ethanol is heated at reflux forthree hours, cooled and poured into dilute aqueous sodium carbonatesolution. The precipitated product is extracted with chloroform and theextracts evaporated to dryness to obtain2-(N-methyl-N-cyclohexylamino)-4-ethoxy-7,8-dimethoxyquinazolinesuitable for use in the next step.

C. To 0.1 mole of the product of Part B in 300 ml. of tetrahydrofuran,anhydrous ammonia is passed through until the mixture has absorbed 0.11mole. The mixture is then stirred for 24 hours at room temperature, thenheated at reflux for two hours and cooled in ice. The precipitated solidis collected by filtration to afford the title compound which may bepurified, if desired, by recrystallization or by chromatography.

D. When 2,6-dichloro-7,8-dimethoxy-4-methyl-thioquinazoline (preparedfrom the corresponding 2,4,6-trichloro- compound and methylmercaptan inthe presence of sodium ethoxide by the procedure of Curd et al., J.Chem. Soc., 775-783 (1947) for 2-chloro-4-methylthioquinazoline) is usedin place of 2,6-dichloro-7,8-dimethoxy-4-ethoxyquinazoline in Part B,above, and the resulting product carried through the above proceduresthe title compound is similarly obtained.

EXAMPLE 27 2-(Morpholin-4-yl)-4-amino-7,8-dimethoxyquinazolinehydrochloride

To 500 ml. of methylethylketone is added 0.1 mole of4-amino-2-chloro-7,8-dimethoxyquinazoline and 0.12 mole of morpholineand the mixture is refluxed overnight. After cooling in ice-water thesolid precipitated is collected by filtration, washed with ether and airdried to obtain the title compound.

When the appropriate starting materials are employed in each case in theabove procedure or any of the procedures of Examples 17, or 22-26, thefollowing compounds are likewise obtained.

    ______________________________________                                         ##STR137##                                                                   Y.sup.1   Y.sup.2     Y.sup.3   m   n                                         ______________________________________                                        H         CH.sub.3 O  CH.sub.3 O                                                                              2   3                                         Cl        C.sub.2 H.sub.5 O                                                                         CH.sub.3 O                                                                              2   2                                         Cl        n-C.sub.3 H.sub.7 O                                                                       H         3   3                                         Cl        CH.sub.3 O  H         2   2                                         Cl        CH.sub.3 O  H         2   3                                         Cl        CH.sub.3 O  CH.sub.3 O                                                                              2   3                                         H         CH.sub.3 O  CH.sub.3 O                                                                              3   3                                         Cl        C.sub.2 H.sub.5 O                                                                         C.sub.2 H.sub.5 O                                                                       3   3                                         ______________________________________                                    

EXAMPLE 28 A. ##STR138##

To a stirred solution of 1.78 g. (0.01 mole)3,4-dimethoxy-2-aminobenzonitrile in 30 ml. of N,N-dimethylformamide isadded 2.88 g. (0.01 mole) ethyl 4-(2-furoyl)piperazin-1-ylformimidatehydrochloride followed by 855 mg. (0.02 mole) of a 56.1% dispersion ofsodium hydride in mineral oil. The reaction mixture is stirred atambient temperature for 30 minutes, and then it is heated to ca. 100° C.and maintained at that temperature for 12 hours. The reaction mixture iscooled to ambient temperature, diluted with an excess of water, and thenextracted with chloroform. The chloroform extract is washed severaltimes with water, dried using anhydrous magnesium sulfate, and thenevaporated to dryness in vacuo. This affords crude7,8-dimethoxy-4-amino-2-[4-(2-furoyl)piperazin-1-yl]quinazoline, whichis purified further by recrystallization from aqueous ethanol.

B. The above procedure is repeated, except that the ethyl4-(2-furoyl)piperazin-1-ylformimidate hydrochloride used therein isreplaced by an equimolar amount of:

ethyl 4-allylpiperazin-1-ylformimidate methanesulfonate,

methyl 4-benzoylpiperazin-1-ylformimidate hydrochloride,

isopropyl 4-(3-furoyl)piperazin-1-ylformimidate hydrochloride,

methyl 4-(allyloxycarbonyl)piperazin-1-ylthioformimidate hydroiodide,

ethyl 4-(2-methylprop-2-enyloxycarbonyl)piperazin-1-ylthioformimidatehydrobromide and

ethyl-4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-ylthioformimidatehydrobromide, respectively.

This affords:

7,8-dimethoxy-4-amino-2-(4-allylpiperazin-1-yl)quinazoline,

7,8-dimethoxy-4-amino-2-(4-benzoylpiperazin-1-yl)quinazoline,

7,8-dimethoxy-4-amino-2-[4-(3-furoyl)piperazin-1-yl]quinazoline,

7,8-dimethoxy-4-amino-2-[4-(allyloxycarbonyl)piperazine-1-yl]quinazoline,

7,8-dimethoxy-4-amino-2-[4-(2-methylprop-2-enyloxycarbonyl)piperazin-1-yl]quinazolineand

7,8-dimethoxy-4-amino-2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-yl]quinazoline,respectively.

C. The procedure of Part A is repeated, except that the3,4-dimethoxy-2-aminobenzonitrile used therein is replaced by anequimolar amount of:

5-chloro-3,4-dimethoxy-2-aminobenzonitrile,

5-chloro-3,4-diethoxy-2-aminobenzonitrile,

5-chloro-4-methoxy-2-aminobenzonitrile, or

5-chloro-4-isopropoxy-2-aminobenzonitrile,

to provide the following compounds, respectively,

    ______________________________________                                         ##STR139##                                                                          Y.sup.2        Y.sup.3                                                 ______________________________________                                               CH.sub.3 O     CH.sub.3 O                                                     C.sub.2 H.sub.5 O                                                                            C.sub.2 H.sub.5 O                                              CH.sub.3 O     H                                                              (CH.sub.3).sub.2 CHO                                                                         H                                                       ______________________________________                                    

EXAMPLE 29

5-Chloro-4-methoxy-2-aminobenzamidine hydrochloride prepared by theprocedure of U.S. Pat. No. 3,935,213 for analogous compounds (0.01 mole)and an equimolar amount of 1-cyano-4-ethoxycarbonylpiperazine alsoprovided in the same reference, are dissolved in 50 ml. of anhydrousethanol and stirred overnight at ambient temperature. A 5 ml. aliquot oftriethylamine is added and the mixture is heated at reflux for 12 hours.The solvent is evaporated to provide4-amino-6-chloro-7-methoxy-2-[4-ethoxycarbonylpiperazin-1-yl]quinazolineas the hydrochloride salt.

EXAMPLE 30

A stirred solution of 24 ml. of concentrated sulfuric acid dissolved inan equal volume of water was cooled to 10°-12° C. and 0.015 mole ofmethallyl4-(4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-1-carboxylateis added in small portions with stirring. The addition is carried out ata rate sufficient to keep the reaction temperature below 20° C. Theresulting mixture is stirred for 15 minutes at 15°-20° C., then for twohours at 10°-15° C. The reaction mixture is diluted with 150 ml. ofice-water and adjusted to pH 10 with sodium hydroxide while maintainingthe temperature below 12° C. After extraction with chloroform, thecombined extracts are washed with water and dried over anhydrous sodiumsulfate. The solvent is evaporated in vacuo and the residuerecrystallized to afford 2-methyl-2-hydroxypropyl4-(4-amino-6-chloro-7,8-dimethoxyquinazolin-2-yl)piperazine-1-carboxylate.

EXAMPLE 312-[4-(3-hydroxypropyl)homopiperazin-1-yl]-4-amino-7,8-dimethoxyquinazolinehydrochloride

A. 2-Chloro-4-amino-7,8-dimethoxyquinazoline, 17 g. andN-formylhomopiperazine, 18.2 g. are added to 170 ml. n-butanol and themixture is refluxed for three hours, cooled and the precipitated solidcollected by filtration. The precipitate is washed with a small amountof ethanol and air-dried. A mixture of 13 g. of this solid and 80 ml. of9% (by weight) hydrochloric acid are heated at reflux for 60 minutes,then allowed to cool and the precipitate of2-homopiperazino-4-amino-7,8-dimethoxyquinazoline is collected andpurified, if desired, by recrystallization.

B. A mixture of 4 g. of triethylamine, 3.0 g. of2-homopiperazino-4-amino-7,8-dimethoxyquinazoline, 4.5 g. of3-bromo-1-propanol and 50 ml. of diethyleneglycol dimethylether isheated at 100°-120° C. with stirring for 16 hours. The reaction mixtureis concentrated in vacuo and the residue made alkaline by addition ofsodium hydroxide solution. The mixture is extracted with chloroform, theextracts washed with water, dried with potassium carbonate and filtered.The filtrate is concentrated, the residue taken up in isopropanol and asolution of hydrogen chloride in isopropanol added until precipitationis complete. The title compound is collected by filtration and dried.

C. When an equivalent amount of 1,3-propandiol monotosylate or1,3-propandiol monomethylsulfonate are employed in place of3-bromo-1-propanol in Part B, above, the results are substantially thesame.

EXAMPLE 32

Employing the appropriate starting materials in each case the followingcompounds are prepared by the procedures of Examples 31 according to theequation ##STR140##

Where a is 1 or m; m and n are 2 or 3 and Q is a leaving group such asBr, Cl, p-toluenesulfonyloxy or methanesulfonyloxy.

    ______________________________________                                        Y.sup.1                                                                           Y.sup.2   Y.sup.3   a   n   R.sup.3                                       ______________________________________                                        Cl  CH.sub.3 O                                                                              H         1   2   CH.sub.3                                      Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   3   CH.sub.3 (CH.sub.2).sub.3                     H   C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       2   2   (CH.sub.3).sub.2 CH(CH.sub.2).sub.3           Cl  C.sub.2 H.sub.5 O                                                                       H         2   2   CH.sub.3 (CH.sub.2).sub.5                     Cl  n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     2   2   CH.sub.2CHCH.sub.2                            H   i-C.sub.3 H.sub.7 O                                                                     i-C.sub.3 H.sub.7 O                                                                     3   2   CH.sub.3 CHCHCH.sub.2                         Cl  CH.sub.3 O                                                                              H         3   2   (CH.sub.3).sub.2 CCHCH.sub.2                  Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              3   3   HC CCH.sub.2                                  H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              3   3   CH.sub.3 C CCH.sub.2                          Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   HOCH.sub.2 CH.sub.2                           Cl  CH.sub.3 O                                                                              H         2   2   (CH.sub. 3).sub.2 C(OH)CH.sub.2               H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   (CH.sub.3).sub.2 C(OH)CH.sub.2 CH.sub.2       Cl  CH.sub.3 O                                                                              H         2   2   cyclopropyl                                   Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   3   cyclopentyl                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              3   3   cyclohexyl                                    Cl  CH.sub.3 O                                                                              H         2   2   cycloheptyl                                   Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   cyclooctyl                                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   3   1-naphthyl                                    H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   2-naphthylmethyl                              H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   4-HOC.sub.6 H.sub.5                           H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2   4-BrC.sub.6 H.sub.4 CH.sub.2                  H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2   3-CH.sub.3 C.sub.6 H.sub.4 CH.sub.2           Cl  CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   3                                                                                  ##STR141##                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   3                                                                                  ##STR142##                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              2   2                                                                                  ##STR143##                                   H   CH.sub.3 O                                                                              CH.sub.3 O                                                                              1   2                                                                                  ##STR144##                                   ______________________________________                                    

EXAMPLE 33

A. 2,3-Dimethoxyaniline obtained by the method of Gibson et al., J.Chem. Soc., 111, 79 (1917), is converted to 2,3-dimethoxy isothiocyanateaccording to the procedure of Dyson et al., J. Chem. Soc., 436 (1927)for analogous compounds.

A solution of 2,3-dimethoxy isothiocyanate (32.1 g., 0.164 mole) in 100ml. of absolute ethanol is added to a stirred solution of1-(2-furoyl)piperazine (29.6 g., 0.164 mole) prepared by the method ofDesai et al., Org. Prep. Proced. Int., 8, 85 (1976) in 350 ml. ofabsolute ethanol and the mixture heated at reflux for 2.5 hours. Thecrude 4-(2-furoyl)piperazine-1-(N-2,3-dimethoxyphenyl)carbothioamide isisolated by evaporation of solvent in vacuo and purified byrecrystallization.

B. To a suspension of 22.0 g. (0.0586 mole) of the product obtained inPart A, above, in 400 ml. of methanol is added methyl iodide 8.32 g.(0.0586 mole). The mixture is stirred at reflux for 2.5 hours, cooled to20° C., 18.7 g. of cyanamide (0.445 mole) is added and the resultingmixture is heated at reflux for an additional 16 hours. The solvent isevaporated in vacuo and the residue made strongly basic with 4.0 Nsodium hydroxide. The alkaline mixture is extracted with chloroform, theextracts washed first with water then with saturated brine and driedover anhydrous magnesium sulfate. The dried extract is concentrated todryness under reduced pressure and the residue crystallized to afford4-(2-furoyl)piperazine-1-[N-cyano-N'-(2,3-dimethoxyphenyl)]carboxamidine.

C. Following the procedure of Part A, above, but employing an equimolaramount of 2,3-dimethoxyphenyl isocyanate in place of 2,3-dimethoxyphenylisothiocyanate, there is obtainedN-(2,3-dimethoxyphenyl)-4-(2-furoyl)-1-piperazinecarboxamide. Reactionof this carboxamide with methyl fluorosulfonate and then with cyanamideaccording to the procedure of Part B, above, provides the same productobtained in Part B.

D. By employing other amines of formula R¹ R² NH, where R¹ and R² are asshown in Examples 18 and 19 or taken together R¹ and R² are ##STR145##as in Examples 10 and 16 or ##STR146## as in Example 14, in theprocedures of Parts A and B or Part C, above, provides compounds of thefollowing formula in like manner. ##STR147## Y¹, Y², Y³ have the valuesshown in Examples 10, 14, 16, 18 and 19.

EXAMPLE 344-Amino-7,8-dimethoxy-2-[4-(2-furoyl)piperazin-1-yl]quinazolinehydrochloride

A. To 10 ml. of phosphorus oxychloride is added with stirring 0.31 g. ofphosphorus pentachloride (1.48 mmoles) followed by 0.54 g. (1.48 mmoles)of4-(2-furoyl)piperazine-1[N-cyano-N'-(2,3-dimethoxyphenyl)]carboxamidineof Example 33, Part B. The reaction mixture is heated at 95°-98° C. for2.5 hours, cooled to 30° C. and excess phosphorus oxychloride isevaporated in vacuo and the residue is triturated with ice water. Theaqueous phase is filtered and the filtrate concentrated in vacuo toprovide the crude product which is purified by crystallization or columnchromatography.

B. When the phosphorus pentachloride used above is replaced by anequimolar amount of hydrogen chloride gas, phosphorus pentabromide,trifluoroacetic acid, ZnCl₂, FeCl₃, AlCl₃ or AlBr₃ and the reactioncarried out at 70°-100° C. for one to three hours the results aresubstantially the same as in Part A.

EXAMPLE 35 Tablets

A tablet base is prepared by blending the following ingredients in theproportion by weight indicated:

Sucrose, U.S.P.--80.3

Tapioca starch--13.2

Magnesium stearate--6.5

Into this base is blended sufficient2-[4-(2-furoyl)-1-piperazinyl]-4-amino-6-chloro-7-methoxyquinazolinehydrochloride to provide tablets containing 0.5, 1.0, 10, 100 and 250mg. of active ingredient.

EXAMPLE 36 Capsules

A blend is prepared containing the following ingredients:

Calcium carbonate, U.S.P.--17.6

Dicalcium phosphate--18.8

Magnesium trisilicate, U.S.P.--5.2

Lactose, U.S.P.--5.2

Potato starch--5.2

Magnesium stearate A--0.8

Magnesium stearate B--0.35

To this blend is added sufficient2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl[piperazin-1-yl]-4-amino-6-chloro-7-methoxyquinazolineto provide formulations containing 0.5, 1.0, 5, 10, 100, 250 and 500 mg.of active ingredient, and the formulations are filled into hard gelatincapsules of a suitable size.

EXAMPLE 37 Injectable Preparation

2-[4-(2-furoyl-1-piperazinyl]-4-amino-6,7-dimethoxyquinazolinehydrochloride is intimately mixed and ground with 2500 g. of sodiumascorbate. The ground dry mixture is filled into vials, sterilized withethylene oxide and the vials sterile stoppered. For intravenousadministration sufficient water is added to the vials to form a solutioncontaining 10 mg. of active ingredient per milliliter.

EXAMPLE 38 Solution

A solution of2-[4-(2-hydroxy-2-methylprop-1-yloxycarbonyl)piperazin-1-yl]-4-amino-6-chloro-7,8-dimethoxyquinazolineor a pharmaceutically acceptable salt thereof is prepared with thefollowing composition:

Effective ingredient--30.22 g.

Magnesium chloride hexahydrate--12.36 g.

Monoethanolamine--8.85 ml.

Propylene glycol--376 g.

Water--94 ml.

The solution has a concentration of 50 mg./ml. and is suitable forparenteral and especially for intramuscular administration.

PREPARATION A 4-Acetoxy-3-methoxybenzaldehyde (IV)

Triethylamine (2.8 liters, 20.1 moles) was added dropwise to a solutionof vanillin (2.00 kg., 13.15 moles) and acetic anhydride (2.6 liters,27.5 moles) in methylene chloride (11.3 liters) maintaining temperaturebelow 25° C. After adding 4-dimethylaminopyridine (20 g.) the solutionwas stirred at room temperature for 30 minutes. The reaction mixture waswashed twice with water, followed by 20% (w/w) hydrochloric acid andbrine. The organic layer was dried over sodium sulfate and concentratedin vacuo to 8 liters. Hexane (15 liters) was added slowly while removingremaining methylene chloride. After cooling, 2.45 kg. (96% yield)product was filtered off. Recrystallization of a small sample fromanhydrous ether gave the acetate as fine yellow needles, M.P. 76°-78° C.

PREPARATION B 4-Acetoxy-3-methoxy-2-nitrobenzaldehyde (V)

Over a period of 1.5 hours 4-acetoxy-3-methoxybenzaldehyde (1120 g.,5.77 moles) was added in small portions to 4 liters of red fuming nitricacid cooled to 0° C. After allowing to stir for one hour below 5° C.,the reaction mixture was added to large amount of ice-water and stirredan additional hour. The resulting yellow product (1130 g., 82% yield)was filtered and washed three times with water, and was sufficientlypure for use directly in the next step. Recrystallization fromether/cyclohexane furnished the pure nitroaldehyde, M.P. 84°-86° C.

PREPARATION C 4-Hydroxy-3-methoxy-2-nitrobenzaldehyde (VI)

4-Acetoxy-3-methoxy-2-nitrobenzaldehyde (1120 g., 4.72 moles) was addedportionwise to a freshly prepared 33% (w/w) NaOH solution (4.5 liters).The resulting slurry was heated on steam bath at 75° C. for 10 minutesafter which it was diluted with 5 liters of water. The reaction mixturewas acidified with 6.4 liters of 6 N hydrochloric acid while cooling,and the resulting product (794 g., 85% yield) was filtered and washedwith water. Recrystallization from ether/cyclohexane gave the desiredproduct as light yellow solid, M.P. 136°-137° C.

PREPARATION D i. 3,4-Dimethoxy-2-nitrobenzaldehyde (VII)

Anhydrous sodium carbonate (957 g., 9.03 moles), toluene (5 liters),4-hydroxy-3-methoxy-2-nitrobenzaldehyde (1424 g., 7.22 moles) anddimethyl sulfate (810 ml., 8.67 moles) were refluxed for 4 hours.Toluene was removed in vacuo and the residual solid dissolved in 5liters of ethyl acetate and 3 liters of water. The organic layer wasseparated, washed with 2 liters of 1 N NaOH and 6 liters of brine,decolorized with charcoal, dried over magnesium sulfate and filtered.Hexane (7.6 liters) was added slowly. After cooling in an ice bath, 1527g. product was obtained by filtration. The crude material wasrecrystallized from ethanol to yield 1187 g. (78%) of the title compoundas a pale yellow solid, 60°-62° C.

ii. By employing diethyl sulfate in place of dimethyl sulfate in theabove procedure, 4-ethoxy-3-methoxy-2-nitrobenzaldehyde is similarlyobtained.

iii. When n-propyl bromide is employed as the alkylating agent thecorresponding 4-n-propyloxy compound is provided.

PREPARATION E 3,4-Dimethoxy-2-nitro-benzoic acid (VIII)

A solution of 823 g. potassium permanganate in about 8.5 liters of H₂ Owas gradually added to a refluxing solution of3,4-dimethoxy-2-nitrobenzaldehyde (550 g., 2.60 moles) in 5.6 liters ofacetone. The reaction mixture was refluxed for four more hours, thenfiltered through diatomaceous earth while hot and the filter cake washedwith hot water. The acetone was removed in vacuo and a small amount ofunreacted solid was filtered off. The aqueous solution was acidifiedwith 2 N hydrochloric acid (1.8 liters) to yield 505 g. (85%) of theessentially pure title compound. Recrystallization from water affordedcolorless crystals, M.P. 200°-202° C.

PREPARATION F 3,4-Dimethoxyanthranilic acid (IXa, R=CH₃)

A solution of 3,4-dimethoxy-2-nitro benzoic acid (1011 g., 4.45 moles)in 14 liters of 1.3 N ammonium hydroxide was reduced at 60 psi inpresence of 60 grams of palladium on barium carbonate. Hydrogen uptakeceased after four hours. The reaction mixture was filtered throughdiatomaceous earth and acidified with glacial acetic acid (1.2 liters)to yield 685 grams (78%) of the anthranilic acid, M.P. 183°-184° C.

PREPARATION G 4-Methoxy anthranilic acid (XXII) i.4-Cyano-3-nitroanisole (XIX)

A saturated solution of sodium nitrite (33.5 g., 0.485 mole) was addeddropwise to a cooled solution of 4-methoxy-2-nitroaniline (68.0 g.,0.404 mole) in 300 ml. water and 94 ml. concentrated hydrochloric acid,while maintaining the temperature at 0° C. and the pH at 6 by additionof sodium carbonate.

The cold solution of diazonium salt was added carefully through ajacketed dropping funnel to a hot solution of cuprous cyanide (36.2 g.,0.404 mole) and potassium cyanide (42.1 g., 0.646 mole) in 500 ml.water, with vigorous stirring and intermittent heating on a steambath.The stirred yellow suspension was heated an additional fifteen minutes.The solid was filtered, dried and dissolved in ethyl acetate, discardingthe undissolved inorganic salts. After decolorization with charcoal,concentration of the ethyl acetate solution yielded 55.1 g. (71%) ofbright yellow-orange crystals, M.P. 135°-7° C.

Analysis, Percent Calcd. for C₈ H₆ N₂ O₃ : C, 53.93; H, 3.39; N, 15.73.Found: C, 53.92; H, 3.47; N, 15.85.

ii. 4-Methoxy-2-nitrobenzoic acid (XXI)

4-Cyano-3-nitroanisole (52.3 g., 0.294 mole) was slowly added to acooled solution of 53 ml. each of acetic acid, water and sulfuric acid.The solution was refluxed for 5 hours, and then diluted with 160 ml.water. After cooling, the resulting solid was filtered and dissolved in10% sodium hydroxide solution. After decolorization with charcoal thesolution was acidified with 6 N HCl, cooled and the yellow product (51.0g., 88% yield) was filtered. An analytical sample was recrystallizedfrom methanol/water, M.P. 196°-7° C.

Analysis, Percent Calcd. for C₈ H₇ NO₅ : C, 48.74; H, 3.58; N, 7.11.Found: C, 48.37; H, 3.57; N, 7.03.

iii. 4-Methoxy anthranilic acid (XXII)

A solution of 4-methoxy-2-nitrobenzoic acid (19.3 g., 97.9 mmole) in 200ml. 1 N NH₄ OH was reduced overnight in presence of 5% Pd/BaCO₃. Thereaction mixture was filtered and acidified with acetic acid to yield15.8 g. (96%) of the anthranilic acid, M.P. 186°-188° C.

iv.

Employing 4-ethoxy-2-nitroaniline or the corresponding 4-n-propoxy- or4-isopropoxy- compounds as starting material in the above procedures thefollowing products are similarly obtained. ##STR148## where Y² isethoxy, n-propoxy or isopropoxy.

PREPARATION H i. Methyl-3,4-dimethoxyanthranilate

Hydrogen chloride was passed into a solution of 3,4-dimethoxyanthranilicacid (100 g., 0.51 mole) in 1.5 liters methanol for 40 minutes. Thereaction mixture was refluxed for 4 days while introducing hydrogenchloride gas intermittently. The solvent was removed in vacuo, and theresidual white solid was dissolved in 500 ml. water, cooled and basifiedto pH 10 with sodium hydroxide solution. After cooling for an additionalhour, the cream color product (87.0 g., 82% yield) was filtered.Recrystallization from methanol furnished pure product, M.P. 66°-67° C.

Analysis, Percent Calcd. for C₁₀ H₁₃ NO₄ : C, 56.86; H, 6.20; N, 6.63.Found: C, 56.56; H, 6.15; N, 6.66.

ii. Methyl-4-methoxyanthranilate

Esterification of 4-methoxy anthranilic acid as described above affordedmethyl-4-methoxyanthranilate, M.P. 77°-79° C., in 77% yield.

PREPARATION I i. 5-Chloro-3,4-dimethoxyanthranilic acid (IXb, R=CH₃)

Sulfuryl chloride (19.3 ml., 0.24 mole) was added dropwise to a cooledsolution of methyl 3,4-dimethoxyanthranilate (42.2 g., 0.20 mole) in 400ml. chloroform at 0° C. (The sulfur dioxide produced was passed througha water trap). After stirring 30 minutes at ambient temperature thesolution was refluxed for 2 hours. The black solution was treated withcharcoal and the solvent was evaporated. The ¹ H-NMR spectrum indicatedthat the black, oily residue was largely the desired intermediate ester.The crude methyl ester was saponified with 400 ml. 5% (w/v) sodiumhydroxide on a steam bath for one hour. After cooling, the basicsuspension was acidified with acetic acid to precipitate a brown solidwhich was filtered and recrystallized from carbon tetrachloride toafford light-brown crystalline product (29.0 g., 63.1% yield), M.P.140°-2° C. [Reported M.P. 142°-3° C., J. Chem. Soc., 4310-4, 1964].

Analysis, Percent Calcd. for C₉ H₁₀ ClNO₄ : C, 46.66; H, 4.35; N, 6.05.Found: C, 46.45; H, 4.45; N, 5.90.

ii. 5-chloro-4-methoxyanthranilic acid (IXc, R=CH₃)

Treatment of methyl-4-methoxyanthranilate with sulfuryl chloride asdescribed above afforded methyl-4-methoxy-5-chloroanthranilate, M.P.,197°-200° C. in 90% yield.

Saponification of methyl-4-methoxy-5-chloro anthranilate yielded5-chloro-4-methoxyanthranilic acid in 64% yield, M.P., 210°-3° C.

Analysis, Percent Calcd for C₈ H₈ ClNO₃ : C, 47.66; H, 4.00; N, 6.95.Found: C, 48.00; H, 4.11; N, 6.94.

When methyl 4-ethoxyanthranilate or methyl 4-n-propyloxyanthranilate arecarried through the above procedure 5-chloro-4-ethoxyanthranilic acidand 5-chloro-4-n-propyloxyanthranilic acid are obtained in like manner.

PREPARATION J

When ethyl vanillin (3-ethoxy-4-hydroxybenzaldehyde) or propyl vanillin,(4-hydroxy-3n-propyloxybenzaldehyde) are employed as starting materialin the procedure of Preparation A in place of vanillin and the resultingproducts carried in turn, through the procedures of Preparation B-F andoptionally chlorination by the procedures of Preparations H and I, thecorresponding compounds of the following formula are similarly obtained.

    ______________________________________                                         ##STR149##                                                                   Y.sup.1                                                                             Y.sup.2   Y.sup.3   Y.sup.1                                                                            Y.sup.2 Y.sup.3                                ______________________________________                                        H     C.sub.2 H.sub.5 O                                                                       C.sub.2 H.sub.5 O                                                                       Cl   C.sub.2 H.sub.5 O                                                                     C.sub.2 H.sub.5 O                      H     n-C.sub.3 H.sub.7 O                                                                     n-C.sub.3 H.sub.7 O                                                                     Cl   n-C.sub.3 H.sub.7 O                                                                   n-C.sub.3 H.sub.7 O                    H     CH.sub.3 O                                                                              C.sub.2 H.sub.5 O                                                                       Cl   CH.sub.3 O                                                                            C.sub.2 H.sub.5 O                      H     n-C.sub.3 H.sub.7 O                                                                     CH.sub.3 O                                                                              Cl   C.sub.2 H.sub.5 O                                                                     CH.sub.3 O                             H     C.sub.2 H.sub.5 O                                                                       CH.sub.3 O                                                                              Cl   n-C.sub.3 H.sub.7 O                                                                   CH.sub.3 O                             H     n-C.sub.3 H.sub.7 O                                                                     C.sub.2 H.sub.5 O                                                                       Cl   n-C.sub.3 H.sub.7 O                                                                   C.sub.2 H.sub.5 O                      ______________________________________                                    

PREPARATION K 3-(m-Trifluoromethylphenyl)piperidine i.N-Benzyl-3-hydroxy-3-(m-trifluoromethylphenyl)piperidine

Under anhydrous conditions, to a mixture of 11 g. of magnesium in 15 ml.of ethyl ether an iodine crystal is added followed by the addition of asolution of 100 g. of m-bromotrifluoromethylbenzene in 300 ml. of etherover a two hour period. The resulting mixture is stirred for two hoursat ambient temperature then cooled to 5° C. A solution of 70 g. ofN-benzyl-3-piperidone in 300 ml. of ether is added at this temperatureover one hour. After stirring for 15 minutes at 5° C. and one hour at20°-25° C., the reaction mixture was poured onto 800 ml. of ice-waterwith stirring. The mixture is filtered, the organic layer extracted with4×100 ml. of 1 N hydrochloric acid and once with brine. The aqueousphase is made alkaline by addition of triethylamine in the cold and theresulting mixture extracted with ethyl acetate. The combined extractsare washed with brine, dried (MgSO₄) and evaporated to dryness. Thecrude product is purified by silica gel chromatography, eluting withcyclohexane/chloroform/triethylamine (85:10:5 by volume) to obtain thedesired product as an orange colored solid.

ii. N-Benzyl-3-acetoxy-3-(m-trifluoromethylphenyl)piperidinehydrochloride

A mixture of 37 g. ofN-benzyl-3-hydroxy-3-(m-trifluoromethylphenyl)piperidine, 220 ml. ofacetic anhydride and 0.3 ml. of concentrated sulfuric acid is heated to110° C. for one hour. After cooling it is poured onto ice-water, theresulting mixture agitated for 15 minutes and made alkaline by additionof sodium hydroxide solution. The mixture is extracted with ethylacetate, the extracts washed with brine, dried (MgSO₄) and evaporated todryness to obtain 39 g. of the free base. This is dissolved in 600 ml.of ethyl acetate, cooled in ice, and 100 ml. of ethanol saturated withhydrogen chloride is added. The solvent is removed by evaporation invacuo and the residue triturated with 200 ml. of ethyl acetate then 200ml. of ethyl ether is added and the mixture allowed to stand overnight.The crystalline title compounds is collected by filtration, washed withether and dried to obtain 36 g., M.P. 206°-207° C.

iii

The product obtained in Part ii is dissolved in 700 ml. of ethanol.Palladium-on-carbon catalyst (40 g.) is added and the mixturehydrogenated at room temperature. When hydrogen uptake ceases thecatalyst is removed by filtration and solvent evaporated in vacuo. Theresulting solid is washed with ether and dried to obtain 21 g. of3-(m-trifluoromethylphenyl)piperidine hydrochloride as colorlesscrystals, M.P. 200° C.

iv

Employing the appropriate cyclic aminoketone, selected fromN-benzyl-3-pyrrolidone, N-benzyl-3-piperidine, N-benzyl-4-piperidone,N-benzyl-4-oxoazacycloheptane and N-benzyl-4-oxo-azacyclooctane, and theappropriate R⁷ Hal (where Hal is Cl, Br or I) in the above procedure thefollowing compounds are obtained in similar manner.

    ______________________________________                                         ##STR150##                                                                   a       n            R.sup.7                                                  ______________________________________                                        1       2            CH.sub.3                                                 1       2            CH.sub.3 (CH.sub.2).sub.5                                1       2            (CH.sub.3).sub.2 CHCH.sub.2                              1       2            C.sub.6 H.sub.5                                          1       2            C.sub.6 H.sub.4 CH.sub.2                                 1       2            4-ClC.sub.6 H.sub.4 CH.sub.2                             1       2            3-CH.sub.3 C.sub.6 H.sub.4                               1       3            (CH.sub.3).sub.2 CH                                      1       3            CH.sub.3 (CH.sub.2).sub.4                                1       3            3-FC.sub.6 H.sub.4                                       1       3            4-CH.sub.3 OC.sub.6 H.sub.4 CH.sub.2                     2       2            4-HOC.sub.6 H.sub.4                                      2       2            3-CH.sub.3 SO.sub.2 C.sub.6 H.sub.4                      2       2            2-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4 CH.sub.2           2       3            CH.sub.3 CH.sub.2                                        2       3            4-CH.sub.3 SO.sub.2 NHC.sub.6 H.sub.4                    2       3            CH.sub.3 (CH.sub.2).sub.3                                2       3            4-CF.sub.3 C.sub.6 H.sub.4 CH.sub.2                      2       3            4-FC.sub.6 H.sub.4                                       3       3            CH.sub.3                                                 3       3            C.sub.6 H.sub.5                                          3       3            C.sub.6 H.sub.5 CH.sub.2                                 3       3            4-CH.sub.3 C.sub.6 H.sub.4                               3       3            3-CH.sub.3 OC.sub.6 H.sub.4                              ______________________________________                                    

PREPARATION L i. 3-Benzoylpiperidine hydrochloride

The method is that of U.S. Pat. No. 3,576,810. To 500 ml. of thionylchloride was added 85.6 g. (0.5 mole) of 1-acetylnipecotic acid. Thestirred mixture was heated at ca. 60° C. for two hours and then thesolvent was evaporated at reduced pressure. The crude acid chloride wastaken up in 200 ml. of dry benzene and the resulting solution addedslowly to a mixture of 133 g. (1.0 mole) of aluminum chloride in 400 ml.of dry benzene. After the addition was complete the mixture was refluxedone hour and then poured onto cracked ice. The organic layer wasseparated and the aqueous layer was extracted with benzene. The combinedextracts were dried over magnesium sulfate and the solvent wasevaporated at reduced pressure. The residual oil which did notcrystallize on cooling was distilled at reduced pressure and thefraction boiling at 160°-170° C./0.05 mm. collected. The crude productweighed 50 g. A mixture of 50 g. of the crude 1-acetyl-3-benzoylpyrrolidine and 200 ml. of 6 N hydrochloric acid wasrefluxed 12 hours, cooled and extracted with benzene. The combinedextracts were washed with water, dried over magnesium sulfate and thesolvent evaporated at reduced pressure. The residual oil weighed 15.1 g.(16% yield). A portion (2.5 g.) of the free base was dissolved in 50 ml.of isopropanol and treated with ethereal hydrogen chloride. The whitecrystalline salt which formed weighed 2.4 g. and melted at 193°-195° C.

ii

Employing the appropriate N-acetylamino acid in place ofN-acetylnipecotic acid and benzene or the appropriately substitutedbenzene in each case, the following compounds are obtained by the aboveprocedure. When R⁸ is OH the starting material is the correspondingacetate and the final product is obtained after hydrolysis, if desired.

    ______________________________________                                         ##STR151##                                                                   a     n         R.sup.8   a   n       R.sup.8                                 ______________________________________                                        1     2         H         2   2       4-CF.sub.3                              1     2         4-Br      2   2       2-CH.sub.3 O                            1     2         4-OH      2   3       4-F                                     1     3         H         2   3       3-CH.sub.3 SO.sub.2                     1     3         2-Cl      3   3       4-OH                                    1     3         4-Cl      3   3       4-F                                     ______________________________________                                    

PREPARATION M N-(1,4-Benzodioxan-2-carbonyl)piperazine

1,4-Benzodioxan-2-carboxylic acid, prepared by oxidation of2-hydroxymethyl-1,4-benzodioxan with potassium permanganate in aqueouspotassium hydroxide at 5°-15° C., was converted to the acid chloride byreaction with thionyl chloride in the standard manner.

A suspension of piperazine (11.88 g.) and sodium acetate (20.30 g.) in amixture of water (70 ml.) and acetone (95 ml.) was stirred at 10°-15°C., then concentrated hydrochloric acid was added (about 35 ml.) untilthe pH of the solution reached 1.5. 1,4-Benzodioxan-2-carbonyl chloride(31.0 g.) and sodium hydroxide (5 N, about 45 ml.) were then addedportionwise while maintaining the temperature at 10°-15° C., the sodiumhydroxide maintaining the pH at 1.7-2.2. After the addition wascomplete, the pH was adjusted to 2.0 by the addition of sodiumhydroxide, the suspension was stirred for a further 30 minutes. Waterwas then added until a homogeneous solution resulted, the acetoneremoved in vacuo, and the aqueous phase was basified to pH 8-9 withsodium hydroxide (5 N), re-extracted with chloroform (3×200 ml.) and theextracts washed with water, dried (MgSO₄) and evaporated in vacuo. Theoily residue was dissolved in ethyl acetate, treated with etherealhydrogen chloride, evaporated in vacuo and the solid residue trituratedwith ether, followed by recrystallization from methanol to giveN-(1,4-benzodioxan-2-carbonyl)piperazine hydrochloride (4.85 g.), M.P.265°-267° C.

PREPARATION N N-Acetyl-4-allyloxypiperidine

A solution of N-acetyl-4-hydroxypiperidine (100 g.) in dimethylformamide(250 ml.) was added dropwise to sodium hydride (38 g., 50% mineral oildispersion) under an atmosphere of nitrogen. The mixture was stirred for2 hours then allyl bromide (93 g.) was added slowly whilst maintainingthe reaction temperature at 25° C. by external cooling. The mixture wasthen stirred at room temperature overnight, diluted with isopropanol (20ml.) and ether (500 ml.), filtered, and evaporated in vacuo.Distillation of the residue gave N-acetyl-4-allyloxypiperidine (108.8g.), B.P. 128° C./2 mm., identified spectroscopically.

PREPARATION O 4-(2-Methoxy-n-propoxy)piperidine

A solution of N-acetyl-4-allyloxypiperidine (6.4 g.) in dry methanol (10ml.) is added dropwise to a stirred suspension of mercuric acetate (11.5g.) in methanol (50 ml.) at room temperature. After 20 minutes themercuric acetate is dissolved and the mixture is stirred for a further40 minutes, cooled in ice-water, and sodium hydroxide (20 ml., 5 N) isthen added. A yellow precipitate formed during the addition. A solutionof sodium borohydride (1.3 g.) in sodium hydroxide (20 ml., 5 N) is thenadded, the mixture stirred for 10 minutes, and acetic acid added tobring the pH to 6. The mixture is filtered from precipitated mercury,the ethanol evaporated in vacuo, and the resulting aqueous phaseextracted with chloroform.

The organic extracts are dried (Na₂ SO₄), evaporated in vacuo, and theresulting crude residue taken up in methanol (50 ml.) and heated underreflux overnight with sodium hydroxide (20 ml., 5 N) and water (20 ml.).Most of the alcohol is then removed in vacuo, the aqueous layerextracted with ether, the extracts dried (Na₂ SO₄) and evaporated toleave a residue. The residue is treated with hydrochloric acid (20 ml.,2 N) and heated on a steam bath for 10 hours. The mixture is then washedwith ether, the aqueous phase basified (Na₂ CO₃), extracted with etherand the organic extract dried (Na₂ SO₄) and evaporated to leave aresidue. Distillation of the residue at reduced pressure affords thetitle compound.

PREPARATION P 4-(2-Hydroxy-n-propoxy)piperidine

N-Acetyl-4-allyloxypiperidine (18 g.) in tetrahydrofuran (30 ml.) wasadded dropwise to a stirred yellow suspension of mercuric acetate (34g.) in a mixture of water (120 ml.) and tetrahydrofuran (120 ml.). Thesuspension dissolved during the addition and the resulting clearsolution was stirred at room temperature for 20 minutes, then sodiumhydroxide (70 ml., 5 N) was added, accompanied by ice/water cooling. Theintermediate thus obtained was then reduced by the addition of sodiumborohydride (2 g.) in sodium hydroxide (40 ml., 5 N), the excess hydridebeing destroyed after 10 minutes with glacial acetic acid. The liquidphase was then decanted off, saturated with sodium choride, the organicphase separated, and the remaining aqueous layer extracted four timeswith chloroform. The combined organic phases were dried (Na₂ SO₄), andevaporated in vacuo to leave a colorless oil (23 g.).

This oil was stirred with 5 N sodium hydroxide at room temperature for16 hours, then at 100° C. for 2 hours. The solution was then extractedwith chloroform (four times), the combined extracts dried (Na₂ SO₄), andevaporated in vacuo to leave a crude crystalline product (16.1 g.). Thiswas taken up in methylene chloride, filtered, evaporated, and theresidue triturated with petroleum ether (B.P. 40°/60° C.) to yield4-(2-hydroxy-n-propoxy)piperidine (11.0 g.), M.P. 55°-57° C. The oxalatesalt thereof was prepared by combining ethereal solutions of the tworeactants and recrystallized from isopropanol, M.P. 104°-105° C.

PREPARATION Q 4-(3-Methoxypropoxy)piperidine

A solution of N-acetyl-4-hydroxypiperidine (30.5 g.) indimethylformamide (200 ml.) is added dropwise to a stirred suspension ofsodium hydride (11.26 g., 50% dispersion in mineral oil) indimethylformamide (300 ml.) under an atmosphere of nitrogen. Thereaction temperature is kept below 30° C. by external cooling and, afterthe addition is complete, stirring is continued for a further 11/4hours. A solution of 1-bromo-3-methoxypropane (35.2 g.) indimethylformamide (100 ml.) is then added dropwise with externalcooling, and the resulting clear solution is stirred at room temperatureovernight. The reaction mixture is then evaporated in vacuo, the residuepartitioned between water and chloroform, the organic extracts dried(Na₂ SO₄) and evaporated to leave a crude residue. The above aqueousphase is saturated with sodium chloride, further extracted withchloroform, and the organic phase is dried (Na₂ SO₄), and evaporated toleave a further residue. This residue is combined with the originalresidue and heated on a steam bath overnight with hydrochloric acid (243ml., 2 N). The reaction mixture is extracted with chloroform to removethe residual mineral oil, the aqueous phase concentrated, basified withsodium hydroxide (pH 12), then reextracted with chloroform. The organicextracts are washed with brine, dried (Na₂ SO₄) and evaporated to affordthe desired product.

We claim:
 1. A compound of the formula ##STR152## wherein Y¹ is chloro,Y² is OR and Y³ is hydrogen or OR, where R is alkyl having from 1 to 3carbon atoms.
 2. The compound according to claim 1 wherein Y² and Y³ areeach methoxy.
 3. The compound according to claim 1 wherein Y² is methoxyand Y³ is hydrogen.